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New Mechanism for Aspirin’s Role in Cancer Prevention

Jul 19, 2016

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It has been known for a while that aspirin has the properties to reduce the risk of colorectal cancer as well as some other cancers. However, there are certain risks associated with its intake like in some cases vehement gastrointestinal bleeding which makes it compulsory to understand how aspirin acts at low doses before it can be prescribed generally as a preventive.

Cornelia Ulrich, PhD, Senior Director of Population Sciences at Huntsman Cancer Institute in Salt Lake City remarked that in the long run the aim is to personalize prevention with aspirin because like everything it can have side effects. The need is to find a tailored solution for people who are most likely to benefit and have the lowest risk of adverse outcomes.

The results of the study were published in the journal of Cancer Epidemiology, Biomarkers, and Prevention. In this study Ulrich and her fellow researchers used an innovative technique, metabolite profiling, to identify a biochemical pathway previously unknown to be regulated by aspirin. It was found by the researchers that aspirin significantly decreases the level of a chemical called 2-hydroxyglutarate in the blood of healthy volunteers and in two colorectal cancer cell lines. It is understood that 2-hydroxyglutarate is a driver of cancer development as increased levels have been found in certain cancers of the blood and brain. There are several ongoing studies that are exploring its ability as a molecule that promotes tumor formation.

Ulrich is very positive about the new study and points out that the study has revealed many evidences that aspirin has a significant role to play in cancer prevention. It does point to a new pathway that needs to be studied further in the context of aspirin.

As a part of the study, the metabolic profiles from the blood of 40 individuals who had taken aspirin for 60 days were studied comprehensively. The design was rigorous; each participant had a phase with and without aspirin. Ulrich remarked that more than 360 metabolites, or small molecule chemicals such as sugars, amino acids, and vitamins, were analyzed. In short, study almost covered most of the known biochemical pathways in the body.

On analyzing the data, it was found that aspirin metabolites were increased in the volunteers as expected (p<0.001), but statistically significant changes were also noted in a metabolite that has been found to drive cancer development, 2-hydroxyglutarate, which was reduced by 12% (p=0.005). In order to follow-up the finding further, the researchers evaluated the levels of 2-hydroxyglutarate in cultured cancer cells after treatment with aspirin in the laboratory. Consistent reductions in 2-hydroxyglutarate, up to 34% was seen in the colorectal cells lines. It was also discovered that the primary metabolite of aspirin, called salicylate, inhibits an enzyme called HOT (hydroxyacidic-oxoacid transhydrogenase) that triggers the production of 2-hydroxyglutarate, which suggests that aspirin is acting on a previously unknown pathway at a concentration comparable to that of individuals treated with aspirin.

Previous studies on the anti-cancer role of aspirin explored its anti-inflammatory and anti-clotting roles as the possible reasons for the cancer-preventive effects. But, this study shows the evidence that other pathways are also involved, particularly at lower aspirin doses.

Ulrich opined that this study suggests that aspirin is playing a key role in interrupting multiple pathways that are linked to cancer development. This study has shed light on evidences that a reduction in 2-hydroxyglutarate may identify a new mechanism for aspirin in cancer prevention. She added that further studies are needed to determine whether the changes in 2-hydroyglutarate levels after aspirin treatment, observed in blood plasma and cultured cancer cells, are also present in colon tissue.

References:

https://healthcare.utah.edu/huntsmancancerinstitute/newsroom/current-press-releases/possible-new-mechanism-for-aspirin-role-cancer-prevention.php

https://medicalxpress.com/news/2015-11-mechanism-aspirin-role-cancer.html

Novel drug approach could improve outlook in high risk leukemia

Jul 18, 2016

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In the United States, about 2,600 children and 1,900 adults develop B-cell acute lymphoblastic leukemia (B-ALL) annually. B-ALL is an aggressive cancer that originates from a type of white blood cell called the B lymphocyte. Due to improvements in chemotherapy in the last five decades, survival rates have improved. However, an estimated 1,000 Americans still die from the disease every year, largely from a subtype called high-risk B-ALL.

A new way to enhance and restore cancer suppressor activity in B-cell acute lymphoblastic leukemia, resulting in better outcomes in a pre-clinical model of the disease has been discovered by researchers at the Penn State College of Medicine, working with Chinese and American colleagues. The researchers are hopeful that the finding could pave the way for a new class of drugs for this and other forms of leukemia. The findings of the study were published in the journal Blood.

It has been observed that patients with high-risk B-ALL relapse after treatment. Dr. Sinisa Dovat, associate professor of pediatrics opined that most of them have one thing in common: impaired activity of a protein called Ikaros that prevents the development and progression of leukemia. He explained that normally, there are two copies of this gene in our DNA. However, in patients with high-risk B-ALL, one copy of the Ikaros gene gets deleted or mutated. Till date, it was not considered possible to enhance the function of Ikaros if one copy was missing or mutated. Present therapies for high-risk B-ALL are aimed at targeting the pathways that promote rather than those that fight leukemia.

In order to gain a better understanding of how impairments in Ikaros function occur in B-ALL, Dovat’s team set out to gain a better understanding of how impairments in Ikaros function occur in B-ALL. They hoped that if this part of the mystery was understood, it could help them develop a drug to target and improve the protein’s activity.

The research team identified one of the mechanisms used by Ikaros to prevent leukemia. Ikaros bind DNA and regulate the activity of a large number of genes in cells. It was found that the ability to control gene activity allows Ikaros to act as a master regulator of the function of blood cells. The protein normally keeps blood cells in check, preventing them from multiplying indefinitely. Dovat explained that if Ikaros’s function is impaired, blood cells escape its control and begin to multiply rapidly, which ultimately leads to high-risk leukemia.

In the study, functional Ikaros protein produced from the remaining normal Ikaros gene was restored with a novel class of drugs that target a specific enzyme called casein kinase 2 or CK2. It is seen that CK2 highly elevates the activity in leukemia and in other types of cancers. Also, it is observed that CK2 directly impairs the function of Ikaros.

Dovat said that high-risk B-ALL is characterized by a missing or mutated Ikaros and the protein produced from the other copy of the Ikaros gene not functioning well due to the high level of CK2.

In the novel strategy designed by Dovat and his team, the new drug also known as the CK2 inhibitor restored Ikaros function and resulted in a strong therapeutic effect in cancer cells from B-ALL patients. The drug also significantly reduced cancer cell proliferation and survival.

Dovat said that the strategy to enhance the function of proteins that flight leukemia is a never-used-before approach. The next step is to study the optimal dose for CK2 inhibitors and determine ways to incorporate the novel drug into current treatments.

References:

https://news.psu.edu/story/384849/2015/12/14/research/novel-drug-approach-could-improve-outlook-high-risk-leukemia

https://medicalxpress.com/news/2015-12-drug-approach-outlook-high-risk-leukemia.html

Researchers take first step in precision medicine for penile cancer

Jul 17, 2016

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In a new study led by researchers at the University of Michigan Comprehensive Cancer Center, it has been identified that potential genetic alterations in penile cancer that could pave the way for targeted treatments.

Penile cancer is characterized by malignant growth on the skin or in the tissues of the penis. Around 95% of penile cancers can be categorized as squamous cell carcinomas. This type of cancer represents about 17 percent of all cancers in men. While a rare disease, the study also dwelled on some of the key similarities with other squamous cell cancers, like lung cancer, head and neck cancer, and cervical cancer. The details of the study were published in Cancer Research recently.

For many patients suffering from this rare form of cancer, surgery is the only option. But in aggressive forms of penile cancer, few therapeutic options exist, targeted therapies in particular. The new study describes a complex landscape that could suggest potential clinical trials of targeted therapies and potential limitations in some patients.

Scott A. Tomlins, M.D., Ph.D., assistant professor of pathology and urology at the University Of Michigan Medical School and a senior author of the study said it is observed that determining the best targeted therapies may be more complicated in penile cancer than in other cancers based on the combinations of genetic changes and variability between primary tumor and metastases.

As a part of the study, next generation sequencing was performed by the researchers on 43 cases of penile squamous cell carcinoma. The cases were of various types differing in stage, grade and subtype. Fourteen samples were matched to include the primary tumor and metastatic tissue. It was found by the researchers that there is a common combination of alterations in the genes KRAS, HRAS and NRAS, as well as alterations in the gene EGFR. Tumors like colon cancer are commonly treated with EGFR inhibitors, while tumors with KRAS or NRAS mutations are resistant to EGFR inhibitors. Importantly, clinical trials are planned using EGFR inhibitors in penile cancers based on anecdotal examples of clinical response.

Sequencing done on the sample used in the study was done using the Oncomine Comprehensive Panel, a new assay that assesses the most common genetic variants across cancer types. The assay is being used in the National Cancer Institute MATCH trial and was developed and validated by researchers at the University of Michigan and Thermo Fisher Scientific.

Tomlins remarked that in colon cancer, there are so few HRAS mutations that their resistance to EGFR inhibitors hasn't been tested. But based on the biology of HRAS, NRAS and KRAS, it is safe to predict that they do cause resistance. As HRAS mutations are relatively common in penile cancer, this alteration may impact the tumor’s response to an EGFR inhibitor in this cancer type.

Also, the researchers found differences between the original primary tumor and metastases in the pelvic lymph nodes. In most cancers, the best therapeutic targets are the same in primary tumors and metastases, which suggests that genetic changes occur early in cancer’s development. As per these findings, aggressive forms of penile cancer mutate as they spread. So, more than one area of tumor may need to be studied to identify the best therapeutic target for a given patient. That means that matching one drug with one mutation based on a single sample in penile cancer is not sufficient. Tomlins remarked that it may be needed to take the genomic profile in total from one or more areas to determine best strategies.

Tomlins remarked that it provides a roadmap to design better, more informed trials for penile cancer. Thanks to this study, now there are some good leads for potential therapeutic and individualized approaches.

References:

https://www.mcancer.org/news/archive/researchers-take-first-step-precision-medicine-penile-cancer

https://medicalxpress.com/news/2015-12-precision-medicine-penile-cancer.html

Researchers Identify Key Biological Markers for Psychotic Disorders

Jul 16, 2016

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With the advent of technology in the medical field a number of medical diagnostic tools have been invented that make it possible to identify the hallmarks of innumerable diseases with simple and reliable tests. These tests are quite precise in portraying the inner workings of the body in detail and helps doctors in singling out the cause of a patient's complaint. This helps in better diagnosis and treatment. However, when it comes to psychiatric diseases, same cannot be said. Even though there have been tremendous advances in technology, there are no objective medical tests to diagnose mental disorders. For example, evidence of schizophrenia cannot be found in a blood sample; psychiatrists cannot see bipolar disorder in an X-ray. Things can however change now.

In a new research by scientists led by faculty at the University of Georgia, a number of biological markers that make it possible to classify mental disorders with greater precision have been identified. The findings are significant as it may one day lead to improved diagnostics and treatments for those suffering from mental illness. The details of the study were published recently in the American Journal of Psychiatry.

Brett Clementz, a professor of psychology in UGA’s Franklin College of Arts and Sciences and the lead author of the study remarked that psychiatry still relies on symptoms as the basis of a diagnosis and it can be difficult at times. So, some means to help psychiatrists more accurately differentiate mental disorders is definitely needed.

To cater to that need, Clementz and his colleagues created an experimental program that uses neurobiological measures instead of symptoms to identify disease types. The focus was exclusively on patients suffering from psychosis. It is a broad category of mental disorder which includes schizophrenia, schizoaffective disorder and bipolar disorder with psychosis. The researchers wanted to see if the existing methods can be improved upon.

Traditionally, the criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders, or DSM is used by mental health professionals to identify specific mental disorders based on observable symptoms. For example, in the case of psychosis, symptoms include hallucinations, delusions, radical changes in personality or a distorted sense of reality.

Clementz remarked that they wanted to try to provide neurobiological underpinnings for DSM-type psychosis diagnoses. More than 700 patients with psychosis along with some of their first degree relatives like a sibling, child or parent and a control group of healthy individuals were recruited. Each of the participants underwent a number of tests in order to assess their cognitive abilities. Researchers used these measures to identify different “biotypes” of mental disorders, which proved to be superior to DSM standards.

Clementz opined that using this new approach they were better able to predict who had family histories of psychoses, structural brain abnormalities and measures of social functioning as compared with DSM standards.

The researchers are positive that it will help in finding more accurate ways of categorizing disease types. Also, this project is likely to inspire a renewed interest in psychiatric drug development, which has suffered due to lack of clear biological targets.

Clementz added that since all of the medications that are used for psychosis have mostly the same mechanism of action, and there are no unique treatments for the various diagnoses. But, if a biological mechanism that contributes to disease can be identified, drug development will get a new lease of life. Clementz also said that there is a lot of work to be done before these measures could be used for new diagnostics, but they are definitely a step closer than they were when the focus was on clinical symptoms alone.

References:

https://medicalxpress.com/news/2015-12-key-biological-markers-psychotic-disorders.html

https://news.uga.edu/releases/article/key-biological-markers-psychotic-disorders-1215/

Researchers Gain Understanding of Why the Brain Makes Mistakes

Jul 15, 2016

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Human brain is made up of a billion nerve cells called neurons and various other types of cells and is the most complex machine ever known. Even after years of research and studies we still do not have a complete understanding of how it works � how it controls every single thing we ever do. In order to unravel one such mysteries of the brain, researchers at the Carnegie Mellon University set out to find out why brain makes mistakes. The study was conducted as part of Carnegie Mellon’s BrainHub, a university initiative that focuses on how the structure and activity of the brain give rise to complex behaviors.

As a part of the study, the results of which were published recently in eLife, the researchers at Carnegie Mellon University investigated the brain’s neural activity during learned behavior. What they found is truly interesting – it has been found that the brain makes mistakes because it applies incorrect inner beliefs, or internal models, about how the world works. The study seems to suggest that when the brain makes a mistake, it actually thinks that it is making the correct decision. The neural signals of the brain are consistent with its inner beliefs, but it might not take into account what is happening in the real world.

Steven Chase, an assistant professor in the Department of Biomedical Engineering and the Center for the Neural Basis of Cognition remarked that human brains are constantly trying to predict how the world works. It does so by building internal models through experience and learning when humans interact with the world. But, it has not yet been possible to track how these internal models affect instant-by-instant behavioral decisions.

An experiment was conducted by the researchers using brain-machine interface � a device that lets the brain control a computer cursor with thoughts only. The researchers studied the brain activity and tried to understand how the brain thinks an action should be performed. As per their observations, the researchers have come to the conclusion that the majority of errors happened due to a mismatch between the subjects’ internal models and reality. They also observed that internal models realigned to better match reality during the course of learning. Byron Yu, an associate professor in the Department of Electrical and Computer Engineering and the Department of Biomedical Engineering remarked that this study brings to our knowledge the most detailed representation of a brain’s inner beliefs that has been identified to date.

The results of the study are quite significant as they have wide-reaching applications. Among the most notable applications is the potential to improve the performance and reliability of current brain-machine interfaces that assist paralyzed patients and amputees. The results can also shed light and help us understand how the brain learns like how we acquire knowledge, learn new language or develop new skills. Since, the results of the study helps us understand why the brain makes mistakes, it can also be a powerful tool in improving the way we learn to perform new tasks.

Matthew Golub, postdoctoral fellow in the Department of Electrical and Computer Engineering cites an example of a doctor trying to learn how to use a new robotic surgical device. If s snapshot of how the doctor thinks the device works can be taken, any mismatch in his or her internal model can be identified and he/she can be more efficiently trained to use the device.

The funding of this study was provided by The National Institute of Child Health and Human Development, the PA Department of Health Research, and the National Science Foundation Integrative Graduate Education and Research Traineeship (IGERT) program.

References:

https://engineering.cmu.edu/media/press/2015/12_08_chase_brain_mistakes.html

https://medicalxpress.com/news/2015-12-gain-brain.html

New Gene That Makes Common Bacteria Resistant To Last-Line Antibiotic Found In Animals and Patients in China

Jul 14, 2016

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As per a new research published in The Lancet Infectious Diseases, a new gene (mcr-1) that makes bacteria to be highly resistant to polymyxins, the last line of antibiotic defence is widespread in Enterobacteriaceae taken from pigs and patients in south China, including strains with epidemic potential. This gene was found on plasmids, mobile DNA and can be easily copied and transferred between different bacteria, and the rate at which it can spread and diversify between different bacterial populations is a matter of high concern.

Professor Jian-Hua Liu from South China Agricultural University in Guangzhou, China expressed his concern and said that the results of the new research are extremely worrying. The polymyxins which includes colistin and polymyxin B were the last class of antibiotics in which resistance was incapable of spreading from cell to cell. It was understood that colistin resistance happened due to chromosomal mutations which made the resistance mechanism unstable and incapable of spreading to other bacteria. The study reveal that the first polymyxin resistance gene that can be easily transmitted between common bacteria has emerged as a result of which pan drug resistance could soon be inevitable.

The finding emerged during routine testing of food animals for antimicrobial resistance in China. The researchers isolated an E coli strain (SHP45) from a pig on an intensive pig farm in Shanghai that exhibited resistance to colistin that could be transferred to another strain. To confirm their finding they collected bacteria samples from pigs at slaughter across four provinces, and from pork and chicken sold in 30 open markets and 27 supermarkets across Guangzhou between 2011 and 2014. Bacteria samples from patients presenting with infections to two hospitals in Guangdong and Zhejiang provinces were also analysed. These samples were then tested for antibiotic susceptibility and the mcr-1 gene using polymerase chain reaction (PCR) and sequencing.

A high prevalence of the mcr-1 gene in E coli isolates from animal (166 of 804) and raw meat samples (78 of 523) was found and the worrying pattern was that the proportion of positive samples increased from year to year. It was also noted that the transfer was very high between E. coli strains. It was also found by the researchers that the mcr-1 gene has the potential to spread into other epidemic pathogenic bacterial species as a result of which diseases from pneumonia to serious blood infections could be widespread.

Professor Jianzhong Shen from China Agricultural University in Beijing, China who is also a co-author of the study said that a relatively low proportion of positive samples were found in humans compared with animals, which suggest that mcr-1 mediated colistin resistance likely originated in animals and subsequently spread to humans.

China is one of the world’s largest users and producers of colistin for agriculture and veterinary use and it seems likely that the selective pressure imposed by increasingly heavy use of colistin here could have led to the acquisition of mcr-1 by E. coli.

The authors opined that even though this trend is emerging in China, it is likely that mcr-1 will emulate other resistance genes like blaNDM-1 and spread worldwide. The use of polymyxins in animals needs to be re-evaluated and close international monitoring and surveillance of mcr-1 in human and veterinary medicine is needed.

China is not the only country that uses colistin in farming. �There are many countries, including in Europe, that use polymyxins in agriculture, and therefore the responsibility to acknowledge and address the use of antibiotics across human and veterinary sectors must be also global. The need of the hour is limitation or cessation of colistin use in agriculture. Failure to do so is likely to create a public health problem of major dimensions.

References:

https://phenomena.nationalgeographic.com/2015/11/21/mcr-gene-colistin/

https://medicalxpress.com/news/2015-11-gene-common-bacteria-resistant-last-line.html

Neuroscientists Reveal How the Brain Can Enhance Connections

Jul 13, 2016

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The human brain is the most complex machine known. Our brain does everything from forming memories to learning new tasks and it does so by encoding the new information and tuning new connections between neurons. These connections are called synapses. Each synapse is characterized by a presynaptic neuron sending chemical signals to one or more postsynaptic receiving cells. In most of the previous studies of how these connections evolve, the focus has been on the role of the postsynaptic neurons. However, in a new research MIT neuroscientists have found that presynaptic neurons also influence connection strength. The details of the study were published in a recent issue of the Journal Neuron.

Troy Littleton, a professor in the departments of Biology and Brain and Cognitive Sciences at MIT, a member of MIT’s Picower Institute for Learning and Memory, and the senior author of the study opined that the mechanism that has been uncovered on the presynaptic side adds to a toolkit that they have for understanding how synapses can change. If it could be understood how synapses change their connections, it would aid scientists better understand neurodevelopmental disorders such as autism, as many of the genetic alterations linked to autism are found in genes that code for synaptic proteins.

The brain has the ability to rewire itself in accordance to changing behavioral condition � a quality known as plasticity. How it happens is still a mystery but it is an ongoing process that continues throughout life.

In the last 30 years of research, scientists have found that strong input to a postsynaptic cell causes it to traffic more receptors for neurotransmitters to its surface, amplifying the signal it receives from the presynaptic cell. This phenomenon termed as long-term potentiation (LTP), occurs following persistent, high-frequency stimulation of the synapse. Long-term depression (LTD), a weakening of the postsynaptic response caused by very low-frequency stimulation, can occur when these receptors are removed. Littleton added that there has been less focus on the presynaptic neuron’s role in plasticity, partly because it is more difficult to study.

In order to investigate how synapses are strengthened, Littleton along with Richard Cho, a research scientist at the Picower Institute and paper’s lead author, studied a type of synapse called neuromuscular junctions, in fruit flies. The researchers stimulated the presynaptic neurons with a rapid series of action potentials over a short period of time. As expected, these cells released neurotransmitter synchronously with action potentials. However, they were surprised to find that mini events as a result of spontaneous release were greatly enhanced well after the electrical stimulation had ended.

Littleton remarked that every synapse in the brain is releasing these mini events, but people have largely ignored them because they only induce a very small amount of activity in the postsynaptic cell. When strong activity pulses were given to these neurons, these mini events suddenly ramped up and they stayed heightened for several minutes before going down.”

It seems enhancement of minis provoke the postsynaptic neuron to release a signaling factor, still unknown, that goes back to the presynaptic cell and activates an enzyme called PKA. This enzyme interacts with a vesicle protein called complexin, which normally acts as a brake, clamping vesicles to prevent release neurotransmitter until it’s needed. Stimulation by PKA modifies complexin so that it releases its grip on the neurotransmitter vesicles, producing mini events.

When these small packets of neurotransmitter are released at elevated rates, they help stimulate growth of new connections, known as boutons, between the presynaptic and postsynaptic neurons. This makes the postsynaptic neuron even more responsive to any future communication from the presynaptic neuron.

The researchers observed this process throughout the flies’ larval development, which lasts three to five days. However, Littleton and Cho demonstrated that acute changes in synaptic function could also lead to synaptic structural plasticity during development.

Littleton’s lab is now trying to figure out more of the mechanistic details of how complexin controls vesicle release.

References:

https://medicalxpress.com/news/2015-11-neuroscientists-reveal-brain.html

https://news.mit.edu/2015/brain-strengthen-connections-between-neurons-1118

New coronary congenital diseases classification aids identification of secondary defects

Jul 12, 2016

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A scheme outlined in a novel European Society of Cardiology (ESC) position paper has revealed that a new classification of coronary congenital diseases is set to aid surgeons identify secondary defects in the operating theater. The details of the same were published recently in Cardiovascular Research. This will also help clinical cardiologists to know what to look for on cardiovascular images. The stressful environment in the operating theater can make it difficult for doctors to spot further defects.

Professor Cristina Basso, chairperson of the ESC Development, Anatomy and Pathology Working Group said that while coronary congenital diseases affect less than 1% of newborns but they are an important cause of myocardial infarction and sudden death particularly in children and competitive athletes. As atherosclerotic coronary artery disease is more common, these coronary congenital conditions are often forgotten in the clinical setting. The heart muscles are nourished by the coronary arteries. If there is any disruption of coronary development during the development of an embryo, coronary congenital defects can occur. Such defects change the blood flow and can adversely affect cardiovascular health.

In the new classification of coronary artery anomalies launched by the paper common points of origin between various coronary defects are explained. If the origin of a primary defect is identified, doctors can evaluate the probability of finding specific secondary defects with an origin mechanistically related to the main anomaly. Professor Basso opined that the paper contains practical information to help clinicians diagnose coronary artery anomalies and prevent devastating complications which includes sudden death.

Dr. José María Pérez-Pomares, first author of the paper said that they have established links between coronary congenital diseases sharing a common mechanism. �He added that when surgeons operate on a certain diagnosed coronary anomaly, it can be often difficult for them to spot further defects in the stressful environment of the operating theatre. So, it can be of significant help to have an idea of the anomalies one can. Another benefit of the new classification is that it will help clinicians using imaging to diagnose coronary artery anomalies and prevent future complications.

Dr. Pérez-Pomares is of the opinion that they have been able to produce this classification because they understand more about how coronary arteries develop in the embryo and how they relate to major diseases. Cardiovascular research scientists can avail of new, updated information on the complex embryonic development of coronary arteries through this classification. It will also throw light on the aetiology of coronary congenital anomalies.

Even though the embryonic origin of the coronary endothelium is a controversial topic in cardiovascular developmental biology, the authors give their expert opinion on it. Since long scientists have wanted to identify a single and unique source for coronary endothelial cells but it is now known that they come from different sources that merge together explained Dr. Pérez-Pomares. It seems that has an impact on what happens to coronary vessels during embryonic development and perhaps also in the adult. Even though it is not mentioned clearly in the paper, the authors seems to be of the opinion that since the origin of cells in the endothelium is heterogeneous, it may play a role in the development of adult coronary disease, as endothelial cells with different origins might respond differentially to pathological stimuli.

The embryonic development of the coronary vascular system is mosaic-like which reflects in the complex spectrum of coronary artery anomalies. Dr. Pérez-Pomares remarked that the more they dig in, the more they have the impression that important events happening in the embryo, such as the activation of regulatory gene networks, signalling molecular pathways and specific cellular mechanisms do have a clear function in adult responses to pathological stimuli.

Looking for ways to beat heart disease? Try this guide.

References:

https://medicalxpress.com/news/2016-01-coronary-congenital-disease-classification-aids.html

https://www.sciencedaily.com/releases/2016/01/160111092409.htm

Insulin producing pancreatic cells created from human skin cells

Apr 26, 2016

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In what can be said to be a significant achievement, the researchers at the Gladstone Institutes and the University of California, San Francisco (UCSF) have successfully converted human skin cells into fully-functional pancreatic cells. In response to changes in glucose levels, the new cells produced insulin. Also, when the cells were transplanted in a mouse model of the disease, they protected the animals from developing diabetes. The details of the study were published recently in the journal Nature Communications.

The results of the study are very encouraging as it shows the significant advancements in cellular reprogramming technology, which will enable scientists to efficiently scale up pancreatic cell production and manufacture trillions of the target cells in a step-wise, controlled manner. The researchers are very positive that this milestone will open avenues for disease modeling and drug screening and bring personalized cell therapy a step closer for patients living with diabetes.

Matthias Hebrok, PhD, director of the Diabetes Center at UCSF and a co-senior author on the study remarked that the results of their study demonstrate for the first time that human adult skin cells can be used to efficiently and rapidly generate functional pancreatic cells that behave similar to human beta cells. He added that this finding open up the opportunity for the analysis of patient-specific pancreatic beta cell properties and the optimization of cell therapy approaches.

Pharmaceutical and genetic molecules were used by the scientists to reprogram skin cells into endoderm progenitor cells. Such cells are early developmental cells that are designated to mature into one of a number of different types of organs. When following this method, the cells don’t have to be taken all the way back to a pluripotent stem cell state, which helps the scientists to turn them into pancreatic cells faster. Similar procedure has been used by the researchers previously to create heart, brain, and liver cells. Once another four molecules were added, the endoderm cells divided rapidly, allowing more than a trillion-fold expansion. The most important thing is that the cells did not display any evidence of tumor formation. They maintained their identity as early organ-specific cells after expansion.

These endoderm cells were then made to progress two more steps � the first step was to transform them into pancreatic precursor cells, and secondly into pancreatic beta cells that are fully-functional. The most significant aspect of these cells was that it protected the mice from developing diabetes in a model of disease. The cells were capable of doing so as they had the critical ability to produce insulin in response to changes in glucose levels.

Saiyong Zhu, PhD, a postdoctoral researcher at the Gladstone Institute of Cardiovascular Disease and the first author of the study opined that their study represents the first successful creation of human insulin-producing pancreatic beta cells using a direct cellular reprogramming method. He added that the final step in the process was the most unique as well as the most difficult because the molecules had not previously been identified that could take reprogrammed cells through the final step in creating functional pancreatic cells in a dish.

This innovative cellular reprogramming and expansion paradigm is by large more sustainable and scalable than previous methods added Sheng Ding, PhD, a senior investigator in the Roddenberry Stem Cell Center at Gladstone and co-senior author on the study. What sets this approach apart from others is the fact that cell production can be significantly increased without compromising the quality control. Since, there are quality checks at various levels; it ensures much greater quality regulation in the manufacturing process of new cells. Thanks to this process, it has enabled us to generate virtually unlimited numbers of patient-matched insulin-producing pancreatic cells.

References:

https://medicalxpress.com/news/2016-01-insulin-producing-pancreatic-cells-human-skin.html

https://www.iflscience.com/health-and-medicine/researchers-have-made-insuling-producing-cells-human-skin-cells

High blood sugar levels could lead to heart attack complications

Apr 25, 2016

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High level of sugar in blood is known to have dangerous consequences on health. But, for the first time researchers at the University of Leicester have demonstrated the process of how high level of sugar in blood can affect the contraction of blood vessels, resulting in potentially dangerous effects on the heart and blood pressure.

Dr. Richard Rainbow who leads the team of researchers from the University’s Department of Cardiovascular Sciences said that when the glucose levels are raised, the blood vessels contract more strongly than they do at ‘normal physiological’ levels.

The contraction and relaxation of blood vessels occur in order to control blood pressure. High blood pressure signifies that the blood vessels are more contracted. The team of researchers made use of electrophysiology and myography techniques to examine the impact of glucose on arterial myocytes � the cells that make up the tissue of our blood vessels, and have identified a mechanism that controls the narrowing of blood vessels.

The reason why heart attacks occur is blocked arteries � these arteries are bestowed with the task of providing blood to the heart to fulfill its nutrient and oxygen needs. In case the level of glucose in blood at the time of a heart attack is high, it could make this block more severe by causing the blood vessel to contract more, leading to a higher risk of complications.

Dr. Richard Rainbow who is also a Lecturer in Cardiovascular Cell Physiology opined that their study have shown that the amount of sugar in the blood changes the behaviour of blood vessels making them contract more than normal. This could result in higher blood pressure, or could reduce the amount of blood that flows through vital organs. He further added that as this was an experimental lab study, we can draw conclusions about cause and effect in a controlled environment. A known signalling protein family, protein kinase C has been identified as a key part of this enhanced contractile response. Through this study, it has also been showed that the normal level of contractile response can be restored, and the effects on the heart can be reversed with inhibitors of these proteins.

This study is the first of its kind that shows direct evidence of blood vessel contraction to glucose, and the potential mechanism behind this contractile response. Many people who suffer a heart attack have high glucose due to the ‘stress response’, which means that even people who are not diabetic may become hyperglycaemic during a heart attack.

The research team working on this study has previously investigated the effects of glucose on the cardiovascular system, diabetes and heart function. Their previous researches have revealed that high glucose from any cause, not just diabetes, was an indicator of a ‘worse outcome’ following a heart attack. One of their research showed that glucose interferes with the normal function of the heart, like arrhythmia and abolishing the built-in protective mechanisms that the heart can activate on stress.

Dr. �Rainbow opined that the findings of the study are significant as it shows that glucose has an important physiological effect on the normal functioning of the cardiovascular system. If such a condition is left untreated for long, results could be life-threatening if left untreated. He added that their data show a clear glucose-induced potentiation of contraction in blood vessels. One way to tackle it is to target the specific types of protein kinase C that are shown to be involved in this. It can provide a novel therapeutic route for improving outcome in ischaemic diseases, such as heart attack or stroke.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said that by targeting PKC to block blood vessel constriction caused by high levels of glucose in the blood, improved treatments can be devised for patients whose recovery from heart attack is complicated by raised glucose levels.

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References:

https://medicalxpress.com/news/2016-01-high-blood-sugar-heart-complications.html

https://www.siasat.com/news/high-blood-sugar-levels-lead-heart-complications-897253/

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