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Posts Tagged ‘Insulin’


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Stroke is a leading cause of death worldwide and the most common cause of long-term disability amongst adults, more particularly in patients with diabetes mellitus and arterial hypertension. Increasing evidence suggests that disordered physiological variables following acute ischaemic stroke, especially hyperglycaemia, adversely affect outcomes.

 

Post-stroke hyperglycaemia is common (up to 50% of patients) and may be rather prolonged, regardless of diabetes status. A substantial body of evidence has demonstrated that hyperglycaemia has a deleterious effect upon clinical and morphological stroke outcomes. Therefore, hyperglycaemia represents an attractive physiological target for acute stroke therapies.

 

However, whether intensive glycaemic manipulation positively influences the fate of ischaemic tissue remains unknown. One major adverse event of management of hyperglycaemia with insulin (either glucose-potassium-insulin infusions or intensive insulin therapy) is the occurrence of hypoglycaemia, which can also induce cerebral damage.

 

Doctors all over the world have debated whether intensive glucose management, which requires the use of IV insulin to bring blood sugar levels down to 80-130 mg/dL, or standard glucose control using insulin shots, which aims to get glucose below 180 mg/dL, lead to better outcomes after stroke.

 

A period of hyperglycemia is common, with elevated blood glucose in the periinfarct period consistently linked with poor outcome in patients with and without diabetes. The mechanisms that underlie this deleterious effect of dysglycemia on ischemic neuronal tissue remain to be established, although in vitro research, functional imaging, and animal work have provided clues.

 

While prompt correction of hyperglycemia can be achieved, trials of acute insulin administration in stroke and other critical care populations have been equivocal. Diabetes mellitus and hyperglycemia per se are associated with poor cerebrovascular health, both in terms of stroke risk and outcome thereafter.

 

Interventions to control blood sugar are available but evidence of cerebrovascular efficacy are lacking. In diabetes, glycemic control should be part of a global approach to vascular risk while in acute stroke, theoretical data suggest intervention to lower markedly elevated blood glucose may be of benefit, especially if thrombolysis is administered.

 

Both hypoglycaemia and hyperglycaemia may lead to further brain injury and clinical deterioration; that is the reason these conditions should be avoided after stroke. Yet, when correcting hyperglycaemia, great care should be taken not to switch the patient into hypoglycaemia, and subsequently aggressive insulin administration treatment should be avoided.

 

Early identification and prompt management of hyperglycaemia, especially in acute ischaemic stroke, is recommended. Although the appropriate level of blood glucose during acute stroke is still debated, a reasonable approach is to keep the patient in a mildly hyperglycaemic state, rather than risking hypoglycaemia, using continuous glucose monitoring.

 

The primary results from the Stroke Hyperglycemia Insulin Network Effort (SHINE) study, a large, multisite clinical study showed that intensive glucose management did not improve functional outcomes at 90 days after stroke compared to standard glucose therapy. In addition, intense glucose therapy increased the risk of very low blood glucose (hypoglycemia) and required a higher level of care such as increased supervision from nursing staff, compared to standard treatment.

 

References:

 

https://www.nih.gov/news-events/news-releases/nih-study-provides-answer-long-held-debate-blood-sugar-control-after-stroke

 

https://www.ncbi.nlm.nih.gov/pubmed/27873213

 

https://www.ncbi.nlm.nih.gov/pubmed/19342845

 

https://www.ncbi.nlm.nih.gov/pubmed/20491782

 

https://www.ncbi.nlm.nih.gov/pubmed/21211743

 

https://www.ncbi.nlm.nih.gov/pubmed/18690907

 

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New Diabetes Treatment Using Smart Artificial Beta Cells

Reporter: Irina Robu, PhD

Researchers from University of North Carolina and North Carolina State University developed a patient friendly option that treats type 1 diabetes and in some cases type two diabetes by using “artificial beta cells, AβCs” to release insulin automatically into the bloodstream when glucose levels rise. These artificial beta cells mimic functions of the body’s natural glucose controllers, the insulin secreting beta cells of the pancreas. The AβCs could be subcutaneously implanted into patients, which would be replaced every few days or by a disposable skin patch. According to the principal investigator, Zhen Gu, PhD at joint UNC/NC State Department of Biomedical Engineering, they plan to optimize the procedure to develop a skin patch delivery system and test diabetes in patients.
Currently, the major problem with the insulin diabetes treatment is that they can’t be delivered efficiently in a pill and the only option is either by injection or a mechanical pump. Delivering the insulin treatments via transplants of pancreatic cells can solve that problem in some cases. Nevertheless, such cell transplants are expensive, require donor cells that are in short supply, require immune-suppressing drugs and fail due to the destruction of the transplanted cells.
Gu’s AβCs are built with a basic version of a normal cell’s two-layered lipid membrane and show a rapid receptiveness to excess glucose levels in lab dish test and diabetic mice without beta cells. The key novelty is what these cells contain insulin-stuffed vesicles. An increase in blood glucose levels leads to chemical changes in the vesicle coating, producing the vesicles to start fusing with the AβC’s outer membrane thus releasing the insulin.

SOURCE

https://news.unchealthcare.org/news/2017/october/smart-artificial-beta-cells-could-lead-to-new-diabetes-treatment

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Alzheimer’s Disease and Diabetes Mellitus

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Unraveling Alzheimer’s:Making Sense of the Relationship between Diabetes and Alzheimer’s Disease1

REFERENCES

[1]

((2015) ) 2015 Alzheimer’s disease facts and figures. Alzheimers Dement 11: , 332–384.

[2]

Hurd MD , Martorell P , Delavande A , Mullen KJ , Langa KM ((2013) ) Monetary costs of dementia in the United States. N Engl J Med 368: , 1326–1334.

[3]

Kavirajan H , Schneider LS ((2007) ) Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: A meta-analysis of randomised controlled trials. Lancet Neurol 6: , 782–792.

[4]

Korczyn AD ((2012) ) Why have we failed to cure Alzheimer’s disease?. J Alzheimers Dis 29: , 275–282.

[5]

Trinh NH , Hoblyn J , Mohanty SU , Yaffe K ((2003) ) Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease – A meta-analysis. JAMA 289: , 210–216.

[6]

Lanctot KL , Herrmann N , Yau KK , Khan LR , Liu BA , Loulou MM , Einarson TR ((2003) ) Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: A meta-analysis. Can Med Assoc J 169: , 557–564.

[7]

Zissimopoulos J , Crimmins E , Clair P St. ((2014) ) The value of delaying Alzheimer disease onset. Conference: Forum for Health Economics and Policy

[8]

de la Monte SM ((2012) ) Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res 9: , 35–66.

[9]

de la Monte SM ((2012) ) Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease. Drugs 72: , 49–66.

[10]

Devi L , Alldred MJ , Ginsberg SD , Ohno M ((2012) ) Mechanisms underlying insulin deficiency-induced acceleration of beta-amyloidosis in a mouse model of Alzheimer’s Disease.e. PLoS One 7: , e32792.

…..

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Insulin, Heat from Sugar, and Research on Diabetes for a Cure

Author: Danut Dragoi, PhD

Insulin

Insulin is a complex molecule, discovered in early 1916 by Paulescu. It is a relative large molecule that has a molecular mass of 5807.57 amu, that corresponds to the following chemical formula C257H383N65O77S6 .

Beyond its well known role in human being, insulin have many interesting structural features.

The picture below shows the structure of the molecule of the insulin. The colored spheres represent the atoms C, H, N, O, and S. This arrangements of atoms results from x-ray proteins crystallography of single crystals obtained from pure insulin.

Insulin molec structure

Image SOURCE: http://pdb101.rcsb.org/motm/14

The yellow spheres in the picture correspond to sulfur atoms that somehow are getting in the structure from a certain source, probably from foods like eggs. It is important to mention that if one component atom is missing in our body, for example Sulfur, the pancreas will not produce the insulin molecule we needed.

Next picture below shows single crystals grown in the lab on Earths as well as in outer space.

Insulin crystals NASA

Image SOURCE: http://science.nasa.gov/science-news/science-at-nasa/1998/notebook/msad22jul98_1/

As we see high quality crystals were obtained in low gravity conditions by NASA. The preferred instrument for producing high quality x-ray diffraction measurements is the synchrotron diffractometer, see link in here.

Heat source from sugar

Metabolic processes require an optimal temperature. . At temperatures higher or lower than 37 °C, enzymes will not function optimally. Too high – they denature opens in a new window, too low – they will slow down the rate at which metabolic processes proceed. A rise of just 2 °C will cause disruption to the internal functioning of a human and should the temperature rise between 43 °C and 45 °C, death may occur. Our tolerance to lower temperatures is much greater. The temperature needs to fall below 23 °C to cause death. So it is important to know about the thermal source generator in our body and its estimated environmental temperature.

The idea of calculating the temperature of human body impose serious computational barriers, but measuring it is not a problem. A simplified approach on this topic can be an approximation with reasonable assumptions. Complex biochemical reactions occur every second in our body. An exact consideration of all chemical reactions in human body is a complicated task, but a simplification can be done using the oxidation of sugar reaction.

Assuming an average body of 70 kg and all sugar from the blood, to be about 5 grams in 5 liters of blood, and considering the density of all blood close to 1g/cubic cm, we can consider the reaction of glucose, Equation (1):

342 g ———————–    2870 kJ

C6H12O6 + 6O2 –> 6CO2 + 6H2O + 2870 kJ ————— (1)

70 g ————————       q=?

The numbers above the chemical reaction of sugar (1) are the molecular mass in grams and the energy released in kJ. Below are the actual amount of sugar in a 70 kg human body and the q, the actual heat generated. Knowing the total amount of sugar in our body, which is approximated as 5 g/5kg (in blood)*5 kg (blood) + 5 g/5 kg *65 kg=70 g sugar and the molecular mass of sugar as 342.2965 g/mol, we have the amount of heat reduced from 2870 kJ* 70/342= 587.4 kJ which represents the heat q in Equation (1). An equation for variable q is shown in Equation (2):

q=mc(T-T’) —————————————–(2)

where we describe the thermal energy needed to raise the body temperature from T’ to T (T'<T). For body temperature T=37 C deg, normal temperature of human body,  m=70 kg-0.15*70 kg-0.15*70 kg=49 kg (where the first factor 0.15 represents the bones and second 0.15 is for the fat in which sugar is assumed not to react with Oxygen as in equation (1) and c= 2624 J/kg/C deg is the minimum specific heat of muscles . Since T’, could be the temperature of the environment in which the human body dissipates the thermal energy, is the only unknown in Equation (1), we can solve for T’, and find T’= 32.4 C deg. The value obtained is in a safe range, above room temperature with some C degrees. The modeling captures well the effect of sugar as an important source of energy for human body.

A study on diabetes indicates that heat treatment improves glucose tolerance. The structure of insulin as a protein suggests the link between our DNA programmed to producing specific proteins needed in our body including insulin. This is a promising avenue for future solutions for a cure of diabetes.

Genetics for a Cure

A recent research on converting fatty tissue into mature beta cells, shows that insulin can be produced by newly created beta like cells raising new expectations for cure of the diabetes.

An interesting posting, discusses in detail the findings of scientists at the Swiss Federal Institute of Technology (ETH) in Zurich, where the investigators added a highly complex synthetic network of genes to the stem cells to recreate precisely the key growth factors involved in this maturation process.

Source

https://en.wikipedia.org/wiki/Nicolae_Paulescu

https://pubchem.ncbi.nlm.nih.gov/compound/16132418

http://pdb101.rcsb.org/motm/14

http://science.nasa.gov/science-news/science-at-nasa/1998/notebook/msad22jul98_1/

http://tle.westone.wa.gov.au/content/file/ea6e15c5-fe5e-78a3-fd79-83474fe5d808/1/hum_bio_science_3a.zip/content/003_homeostasis/page_06.htm

http://hypertextbook.com/facts/LenaWong.shtml

http://sciencelearn.org.nz/Contexts/Digestion-Chemistry/Looking-Closer/Mitochondria-cell-powerhouses

http://hyperphysics.phy-astr.gsu.edu/hbase/organic/sugar.html

https://www.google.com/#q=density+of+blood

http://sciencelearn.org.nz/Contexts/Digestion-Chemistry/Looking-Closer/Mitochondria-cell-powerhouses

https://www.google.com/#q=molecular+mass+of+sugar

https://www.google.com/#q=percent+of+weight+bones+in+human+body

http://www.itis.ethz.ch/virtual-population/tissue-properties/database/heat-capacity/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646055/

http://www.genengnews.com/gen-news-highlights/a-new-use-for-love-handles-insulin-producing-beta-cells/81252612/

 

 

 

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Breakthrough Research on Encapsulated pancreatic cells offer possible new diabetes treatment.

Reporter: Eveline B. Cohn, PhD

No more insulin injections?

Encapsulated pancreatic cells offer possible new diabetes treatment.

It is known that in patients with Type 1 diabetes the immune system attacks the pancreas, and the monitoring of blood sugar becomes really difficult. Lately the research showed a possibility of replacing the pancreatic islets cells with healthy cells to take over glucose monitoring and insulin release. However the immune system attacked the transplanted cells, patients being obliged to take immunosuppressant drugs for the rest of their life.
Now , a new advance in this type of research by Boston Children’s Hospital designed a material that was used to encapsulate human islet before transplanted them. In animal testing it was showed that the encapsulated human cells could cure diabetes for up to six months without provoking an immune response.
This approach “has the potential to provide diabetics with a new pancreas that is protected from the immune system, which allow them to control their blood sugar without taking drugs. That’s the dream” says Daniel Anderson, The Samuel A Goldblith Associate Professor in MIT’s Department of Chemical Engineering, A member of MIT’s Koch Institute for integrative Cancer research and Institute for Medical Engineering and Science (IMES), and a research fellow in the department of Anesthesiology at Boston Children’s Hospital
The JDRF director Julia Greenstein, Anderson, Langer and colleagues explored a chemical derivative originally isolated from brown algae to encapsulate the cells without harming them, allowing sugar and proteins to go through, thus permitted to test the glucose level after transplantation of the encapsulated cells. The research was published in Nature Medicine and Nature Biotechnology. Researchers from Harvard University, University of Illinois at Chicago and Joslin Diabetes Center and University of Massachusetts Medical school also contributed to this research.
Previous research has shown that when alginate capsules are implanted in primates and humans, scar tissue builds up around the capsules, making the device ineffective. MIT/Children Hospital try to modify alginate make it less likely to provoke this kind of immune response.

A stealth material surface, shown here, has been engineered to provide an “invisibility cloak” against the body’s immune system cells. In this electron microscopy image, you can see the material's surface topography.

With The Courtesy of The Researchers

“We decided to take an approach where you cast a very wide net and see what you can catch,” says Arturo Vegas, a former MIT and Boston Children’s Hospital postdoc who is now an assistant professor at Boston University. Vegas is the first author of the Nature Biotechnology paper and co-first author of the Nature Medicine paper. “We made all these derivatives of alginate by attaching different small molecules to the polymer chain, in hopes that these small molecule modifications would somehow give it the ability to prevent recognition by the immune system.”
800 alginate derivatives were screened . Further, the known triazole thiomorpholine dioxide (TMTD) have been chosen to be tested in diabetic mice. They chose a strain of mice with a strong immune system and implanted human islet cells encapsulated in TMTD into a region of the abdominal cavity known as the intraperitoneal space.
The pancreatic islet cells used in this study were generated from human stem cells using a technique recently developed by Douglas Melton, a professor at Harvard University who is an author of the Nature Medicine paper.
Following implantation, the cells immediately began producing insulin in response to blood sugar levels and were able to keep blood sugar under control for the length of the study, 174 days.
“The really exciting part of this was being able to show, in an immune-competent mouse, that when encapsulated these cells do survive for a long period of time, at least six months,” says Omid Veiseh, a senior postdoc at the Koch Institute and Boston Children’s hospital, co-first author of the Nature Medicine paper, and an author of the Nature Biotechnology paper. “The cells can sense glucose and secrete insulin in a controlled manner, alleviating the mice’s need for injected insulin.”
The researchers also found that 1.5-millimeter diameter capsules made from their best materials (but not carrying islet cells) could be implanted into the intraperitoneal space of nonhuman primates for at least six months without scar tissue building up.
“The combined results from these two papers suggests that these capsules have real potential to protect transplanted cells in human patients,” says Robert Langer, the David H. Koch Institute Professor at MIT, a senior research associate at Boston’s Children Hospital, and co-author on both papers. “We are so pleased to see this research in cell transplantation reach these important milestones.”
Cherie Stabler, an associate professor of biomedical engineering at the University of Florida, says this approach is impressive because it tackles all aspects of the problem of islet cell delivery, including finding a source of cells, preventing an immune response, and developing a suitable delivery material.
“It’s such a complex, multipronged problem that it’s important to get people from different disciplines to address it,” says Stabler, who was not involved in the research. “This is a great first step towards a clinically relevant, cell-based therapy for Type I diabetes.”

VIEW VIDEO

VIDEO SOURCE

https://www.youtube.com/watch?v=cw3EbB8DAq8

At this point the researchers are thinking of using their new material in non human primates and eventually performing clinical trials in diabetic patients. “Our goal is to continue to work hard to translate these promising results into a therapy that can help people,” Anderson says.
“Being insulin-independent is the goal,” Vegas says. “This would be a state-of-the-art way of doing that, better than any other technology could. Cells are able to detect glucose and release insulin far better than any piece of technology we’ve been able to develop.”
In their research they found out that the new material works best with molecules containing triazole group- a ring containing two atoms of Carbon and three of N. However, they suspect that in this particular case it may interfere with the immune system’s ability to recognize the material as foreign.

The work was supported, in part, by the JDRF, the Leona M. and Harry B. Helmsley Charitable Trust, the National Institutes of Health, and the Tayebati Family Foundation.
Other authors of the papers include MIT postdoc Joshua Doloff; former MIT postdocs Minglin Ma and Kaitlin Bratlie; MIT graduate students Hok Hei Tam and Andrew Bader; Jeffrey Millman, an associate professor at Washington University School of Medicine; Mads Gürtler, a former Harvard graduate student; Matt Bochenek, a graduate student at the University of Illinois at Chicago; Dale Greiner, a professor of medicine at the University of Massachusetts Medical School; Jose Oberholzer, an associate professor at the University of Illinois at Chicago; and Gordon Weir, a professor of medicine at the Joslin Diabetes Center.

SOURCE

http://news.mit.edu/2016/pancreatic-cells-diabetes-treatment-insulin-injections-0125?elq=6d9b90a822f04183bd0b059d36eb2b7a&elqCampaignId=9&elqaid=14548&elqat=1&elqTrackId=d91b7d01a9d14b199e41b4deb2c10ac6

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Immunopathogenesis Advances in Diabetes and Lymphomas

Larry H Bernstein, MD, FCAP, Curator

LPBI

 

 

 Science team says they’ve taken another step toward a potential cure for diabetes

Wednesday, January 27, 2016 | By John Carroll
Building on years of work on developing new insulin-producing cells that could one day control glucose levels and cure diabetes, a group of investigators led by scientists at MIT and Boston Children’s Hospital say they’ve developed a promising new gel capsule that protected the cells from an immune system assault.

Dr. Jose Oberholzer, a professor of bioengineering at the University of Illinois at Chicago, tested a variety of chemically modified alginate hydrogel spheres to see which ones would be best at protecting the islet cells created from human stem cells.

The team concluded that 1.5-millimeter spheres of triazole-thiomorphine dioxide (TMTD) alginate were best at protecting the cells and allowing insulin to seep out without spurring an errant immune system attack or the development of scar tissue–two key threats to making this work in humans.

They maintained healthy glucose levels in the rodents for 174 days, the equivalent to decades for humans.

“While this is a very promising step towards an eventual cure for diabetes, a lot more testing is needed to ensure that the islet cells don’t de-differentiate back toward their stem-cell states or become cancerous,” said Oberholzer.

Millions of diabetics have effectively controlled the chronic disease with existing therapies, but there’s still a huge unmet medical need to consider. While diabetes companies like Novo ($NVO) like to cite the fact that a third of diabetics have the disease under control, a third are on meds but don’t control it well and a third haven’t been diagnosed. An actual cure for the disease, which has been growing by leaps and bounds all over the world, would be revolutionary.

Their study was published in Nature Medicine.

– here’s the release
– get the journal abstract

 

Long-term glycemic control using polymer-encapsulated human stem cell–derived beta cells in immune-competent mice

Arturo J Vegas, Omid Veiseh, Mads Gürtler,…, Robert Langer & Daniel G Anderson

Nature Medicine (2016)   http://dx.doi.org:/10.1038/nm.4030

The transplantation of glucose-responsive, insulin-producing cells offers the potential for restoring glycemic control in individuals with diabetes1. Pancreas transplantation and the infusion of cadaveric islets are currently implemented clinically2, but these approaches are limited by the adverse effects of immunosuppressive therapy over the lifetime of the recipient and the limited supply of donor tissue3. The latter concern may be addressed by recently described glucose-responsive mature beta cells that are derived from human embryonic stem cells (referred to as SC-β cells), which may represent an unlimited source of human cells for pancreas replacement therapy4. Strategies to address the immunosuppression concerns include immunoisolation of insulin-producing cells with porous biomaterials that function as an immune barrier56. However, clinical implementation has been challenging because of host immune responses to the implant materials7. Here we report the first long-term glycemic correction of a diabetic, immunocompetent animal model using human SC-β cells. SC-β cells were encapsulated with alginate derivatives capable of mitigating foreign-body responses in vivo and implanted into the intraperitoneal space of C57BL/6J mice treated with streptozotocin, which is an animal model for chemically induced type 1 diabetes. These implants induced glycemic correction without any immunosuppression until their removal at 174 d after implantation. Human C-peptide concentrations and in vivo glucose responsiveness demonstrated therapeutically relevant glycemic control. Implants retrieved after 174 d contained viable insulin-producing cells.

Subject terms: Regenerative medicine  Type 1 diabetes

Figure 1: SC-β cells encapsulated with TMTD alginate sustain normoglycemia in STZ-treated immune-competent C57BL/6J mice.close

(a) Top, schematic representation of the last three stages of differentiation of human embryonic stem cells to SC-β cells. Stage 4 cells (pancreatic progenitors 2) co-express pancreatic and duodenal homeobox 1 (PDX-1) and NK6 homeobox 1…

 

Potential Cure for Diabetes Discovered  
http://www.rdmag.com/news/2016/01/potential-cure-diabetes-discovered   01/27/2016

Two new scientific papers published on Monday demonstrated tools that could result in potential therapies for patients diagnosed with type 1 diabetes, a condition in which the immune system limits the production of insulin, typically in adolescents.  See —

Bubble Technique Could Create Type 1 Diabetes Therapy

http://www.dddmag.com/news/2016/01/bubble-technique-could-create-type-1-diabetes-therapy

Two new scientific papers published on Monday demonstrated tools that could result in potential therapies for patients diagnosed with type 1 diabetes, a condition in which the immune system limits the production of insulin, typically in adolescents.

Previous treatments for this disease have involved injecting beta cells from dead donors into patients to help their pancreas generate healthy-insulin cells, writes STAT. However, this method has resulted in the immune system targeting these new cells as “foreign” so transplant recipients have had to take immune-suppressing medications for the rest of their lives.

The first paper published in the journal Nature Biotechnology explained how scientists analyzed a seaweed extract called alginate to gauge its effectiveness in supporting the flow of sugar and insulin between cells and the body. An estimated 774 variations were tested in mice and monkeys in which results indicated only a handful could reduce the body’s response to foreign invaders, explains STAT.

The other paper in the journal Nature Medicine detailed a process where scientists developed small capsules infused with alginate and embryonic stem cells. A six-month observation period revealed this “protective bubble” technique “began to produce insulin in response to blood glucose levels” after transplantation in mice subjects with a condition similar to type 1 diabetes, reports Gizmodo.

Essentially, this cured the mice of their diabetes, and the beta cells worked as well as the body’s own cells, according to the researchers. Human trials could still be a few years away, but this experiment could yield a safer alternative to insulin injections.

 

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates

Arturo J Vegas, Omid Veiseh, Joshua C Doloff, et al.

Nature Biotechnology (2016)    http://dx.doi.org:/10.1038/nbt.3462

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient1, 2, 3, 4, 5, 6. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.

 

Video 1: Intravital imaging of 300 μm SLG20 microcapsules.

Video 2: Intravital imaging of 300 μm Z2-Y12 microcapsules.

Video 3: NHP Laparoscopic procedure for the retrieval of Z2-Y12 spheres.

 

Clinical Focus on Follicular Lymphoma: CAR T-Cells Active in Relapsed Blood Cancers

MedPage Today

CAR T-Cells Active in Relapsed Blood Cancers

Complete responses in half of patients

by Charles Bankhead

Patients with relapsed and refractory B-cell malignancies have responded to treatment with modified T-cells added to conventional chemotherapy, data from an ongoing Swedish study showed.

Six of the first 11 evaluable patients achieved complete responses with increasing doses of chimeric antigen receptor (CAR)-modified T-cells that target the CD19 antigen, although two subsequently relapsed.

Five of the six responding patients received preconditioning chemotherapy the day before CAR T-cell infusion, in addition to chemotherapy administered up to 90 days before T-cell infusion to reduce tumor-cell burden. The remaining five patients received only the earlier chemotherapy, according to a presentation at the inaugural International Cancer Immunotherapy Conference in New York City.

“The complete responses in lymphoma patients despite the fact that they received only low doses of preconditioning compared with other published data surprised us,” Angelica Loskog, PhD, of Uppsala University in Sweden, said in a statement. “The strategy of both providing tumor-reductive chemotherapy for weeks prior to CAR T-cell infusion combined with preconditioning just before CAR T-cell infusion seems to offer promise.

CAR T-cells have demonstrated activity in a variety of studies involving patients with B-cell malignancies. Much of the work has focused on patients with leukemia, including trials in the U.S. B-cell lymphomas have proven more difficult to treat with CAR T-cells because the diseases are associated with higher concentration of immunosuppressive cells that can inhibit CAR T-cell activity, said Loskog. Moreover, blood-vessel abnormalities and accumulation of fibrotic tissue can hinder tumor penetration by therapeutic T-cells.

Each laboratory has its own process for modifying T-cells. Loskog and colleagues in Sweden and at Baylor College of Medicine in Houston have developed third-generation CAR T-cells that contain signaling domains for CD28 and 4-1BB, which act as co-stimulatory molecules. In preclinical models, third-generation CAR T-cells have demonstrated increased activation and proliferation in response to antigen challenge. Additionally, they have chosen to experiment with tumor burden-reducing chemotherapy, a preconditioning chemotherapy to counter the higher immunosuppressive cell count in lymphoma patients.

Loskog reported details of an ongoing phase I/IIa clinical trial involving patients with relapsed or refractory CD19-positive B-cell malignancies. Altogether, investigators have treated 12 patients with increasing doses (2 x 107 to 2 x 108 cells/m2) of CAR T-cells. One patient (with mixed follicular/Burkitt lymphoma) has yet to be evaluated for response. The remaining 11 included three patients with diffuse large B-cell lymphoma (DLBCL), one with follicular lymphoma transformed to DLBCL, two with chronic lymphocytic leukemia, two with mantle cell lymphoma, and three with acute lymphoblastic leukemia.

All of the patients with lymphoma received standard tumor cell-reducing chemotherapy, beginning 3 to 90 days before administration of CAR T-cells. Beginning with the sixth patient in the cohort, patients also received preconditioning chemotherapy (cyclophosphamide/fludarabine) 1 to 2 days before T-cell infusion to reduce the number and activity of immunosuppressive cells.

Cytokine release syndrome is a common effect of CAR T-cell therapy and occurred in several patients treated. In general, the syndrome has been manageable and has not interfered with treatment or response to the modified T-cells.

On the basis of the data produced thus far, the investigators have proceeded with patient evaluation and enrollment. They have already begun cell production for the next patient that will be treated with autologous CAR T-cells.

Although laboratories have their own cell production techniques, the treatment strategy has broad applicability to the treatment of B-cell malignancies, said Loskog.

“The results using different CARs and different techniques for manufacturing them is very similar in the clinic, in terms of initial complete response,” she told MedPage Today. “By using 4-1BB as a co-stimulator in the CAR intracellular region, it seems possible to achieve long-term complete responses in some patients. However, preconditioning of the patients with chemotherapy to reduce the regulatory immune cells seems crucial for effect.”

In an effort to manage the effect of patients’ immunosuppressive cells, the investigators have begun studying each the immune profile before and after treatment. Preliminary results suggest that the population of immunosuppressive cells increases over time, which has the potential to interfere with CAR T-cell responses.

“Especially for lymphoma, it may be crucial to deplete such cells prior to CAR infusion,” said Loskog. “It may even be necessary with supportive treatment for some time after CAR T-cell infusion. A supportive treatment needs to specifically regulate the suppressive cells while sparing the effect of CARs.”

The immunotherapy conference is jointly sponsored by the American Association for Cancer Research, the Cancer Research Institute, the Association for Cancer Immunotherapy, and the European Academy of Tumor Immunology.

 

PET-CT Best for FL Response Assessment

PET-CT associated with better progression-free and overall survival rates in follicular lymphoma.

Kay Jackson

PET-CT (PET) rather than contrast-enhanced CT scanning should be considered the new gold standard for response assessment after first-line rituximab therapy for high-tumor burden follicular lymphoma (FL), a pooled analysis of a central review in three multicenter studies indicated.

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Clinical Trials Could Lead to FDA Approval for Artificial Pancreas

 Reported by: Irina Robu, PhD

Approximately 1.25 million American have type 1 diabetes accroding to the U.S. Centers for Disease Control and Prevention. A device that automatically monitors and regulates blood-sugar levels in people with type 1 diabetes developed by University of Virginia School of Medicine undergo two clinical trials starting early 2016.

The goal of the artificial pancreas is to eliminate the need for people with type 1 diabetes to stick their fingers multiple times daily to check their blood-sugar levels and to inject insulin manually.The artificial pancreas is designed to oversee and adjust insulin delivery as needed. At the center of the artificial pancreas platform is a reconfigured smartphone running advanced algorithms that is linked wirelessly to a blood-sugar monitor and an insulin pump, as well as a remote-monitoring site. People with the artificial pancreas can also access assistance via telemedicine.

Beneficial results from these long-term clinical trials examining how the artificial pancreas works in real-life settings could lead the U.S. Food and Drug Administration and other international regulatory groups to approve the device for use by people with type 1 diabetes, whose bodies do not produce enough insulin. The trials will conducted at nine locations in the U.S. and Europe sustained by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

The first study – the International Diabetes Closed-Loop trial – will test technology developed at UVA by a research team led by Boris Kovatchev, director of the UVA Center for Diabetes Technology. That technology has been refined for clinical use by TypeZero Technologies, a startup company in Charlottesville that has licensed the UVA system.
The second trial will examine a new control algorithm developed by the team of Dr. Francis Doyle III at the Harvard John A. Paulson School of Engineering and Applied Sciences to test whether it further improves control of blood-sugar levels.

Along with UVA, the artificial pancreas will be tested at eight additional sites: Harvard University, Mount Sinai School of Medicine, Mayo Clinic, University of Colorado, Stanford University, University of Montpellier in France, University of Padova in Italy and Academic Medical Center at the University of Amsterdam in The Netherlands.

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