New discovery could lead to ‘fundamental’ change in leukemia treatment
Researchers have identified a new cell mechanism that could lead to a fundamental change in the diagnosis and treatment of leukaemia.
A team in the University of Kent’s pharmacy school conducted a study that discovered that leukaemia cells release a protein, known as galctin-9, that prevents a patient’s own immune system from killing cancerous blood cells.
Acute Myeloid Leukaemia (AML) – a type of blood cancer that affects over 250,000 people every year worldwide – progresses rapidly because its cells are capable of avoiding the patient’s immune surveillance. It does this by inactivating the body’s immune cells, cytotoxic T lymphocytes and natural killer (NK) cells.
Existing treatment strategies consist of aggressive chemotherapy and stem cell transplantation, which often do not result in effective remission of the disease. This is because of a lack of understanding of the molecular mechanisms that allow malignant cells to escape attack by the body’s immune cells.
Now the researchers at the Medway School of Pharmacy, led by Dr Vadim Sumbayev, Dr Bernhard Gibbs and Professor Yuri Ushkaryov, have found that leukaemia cells – but not healthy blood cells – express a receptor called latrophilin 1 (LPHN1). Stimulation of this receptor causes these cancer cells to release galectin-9, which then prevents the patient’s immune system from fighting the cancer cells.
The discovery of this cell mechanism paves the way for new ‘biomarkers’ for AML diagnosis, as well as potential targets for AML immune therapy, say the researchers.
‘Targeting this pathway will crucially enhance patients own immune defences, helping them to eliminate leukaemia cells’, said Dr Sumbayev. He added that the discovery has the potential to also be beneficial in the treatment of other cancers.
Article: The Tim-3-galectin-9 Secretory Pathway is Involved in the Immune Escape of Human Acute Myeloid Leukemia Cells, Vadim V. Sumbayev et al., EBioMedicine, doi: 10.1016/j.ebiom.2017.07.018, published online 19 July 2017.
Source: http://www.medicalnewstoday.com/releases/318700.php
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Could Type 2 Diabetes Be Transmissible ?
A new study has found a prion-like mechanism that drives type 2 diabetes.
Although the findings are preliminary, new research suggests that type 2 diabetes may be transmissible in a way that is similar to prion disorders such as “mad cow disease.”
Type 2 diabetes affects more than 420 million people worldwide, its causes remain largely unknown. However, a new study has uncovered a novel mechanism that may drive the disease. The discovery could change the way we approach type 2 diabetes, both from a research perspective and from a therapeutic point of view.
More specifically, the study investigates the possibility that type 2 diabetes might be caused by a misfolding of islet amyloid polypeptide protein (IAPP).
The research was led by Claudio Soto at the McGovern Medical School in Houston, TX, which is part of the University of Texas Health Science Center in Houston.
The findings, published in The Journal of Experimental Medicine, show that type 2 diabetes shares similarities with a group of transmissible neurodegenerative diseases known as “prion diseases.”
Examples of such diseases include bovine spongiform encephalopathy – popularly known as “mad cow disease” – or its human equivalent, Creutzfeldt-Jakob disease.
IAPP in type 2 diabetes
Previous research has shown that up to 80 percent of all type 2 diabetes patients have an accumulation of IAPP in the pancreas’ islets. These are small clusters of cells inside the pancreas, which contain, among other cells, insulin-producing beta cells.
IAPP is a peptide hormone that is secreted together with insulin by the pancreatic beta cells. While the effect of this excessive IAPP in type 2 diabetes is not fully known, it is believed that it damages the beta cells, stopping them from producing the insulin that the body needs to lower blood sugar levels.
Examining the ‘prion-like’ mechanism
Prion diseases get their name from the excessive accumulation of an abnormal form of a so-called prion protein – that is, a cellular protein that occurs naturally in the body. This abnormal form of the prion protein is generated through a mechanism called misfolding. Normally, proteins gain their functional shape through a process referred to as folding.
But when they do not fold correctly, or “misfold,” these proteins clump together, forming aggregates such as the ones found in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and other neurodegenerative conditions.
Moreover, in some of these diseases, a few of the misfolded proteins can act as “seeds” that trigger other proteins to misfold. In these diseases, the seeds – or abnormal prions – can transmit from one person, or animal, to another.
Prion-like mechanism may cause diabetes
For their research, Soto and his team designed a mouse model wherein the mice’s pancreases were genetically modified to express human IAPP.
They injected misfolded IAPP into these mice and found that it triggered the formation of protein deposits, or aggregates, in the mice’s pancreases.
Additionally, the mice developed type 2 diabetes symptoms within weeks of having IAPP injected: they lost beta cells and had high blood sugar levels.
Furthermore, the researchers examined the effect of misfolded IAPP in pancreatic islet cultures, taken from healthy humans. There, too, misfolded IAPP triggered the formation of large IAPP aggregates.
Therefore, it appears that misfolded IAPP can, in fact, cause aggregates in a way that is similar to infectious prion disorders.
Although there have been numerous cases of patients who developed type 2 diabetes after organ transplantation, the authors caution against jumping to conclusions.
“Considering the experimental nature of the models and conditions utilized in this study, the results should not be extrapolated to conclude that type 2 diabetes is a transmissible disease in humans without additional studies,” Soto warns.
He further comments on the significance of the findings, saying, “Until now, this concept has not been considered. Our data, therefore, [open] up an entirely new area of research with profound implications for public health.”
“Perhaps more important than a putative inter-individual transmission, the prion-like mechanism may play a key role in the spreading of the pathology from cell to cell or islet to islet during the progression of type 2 diabetes.” – Claudio Soto
Source: http://www.medicalnewstoday.com/articles/318725.php
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Organ donation up 4-fold in India, but still a long way to go
Of the 85,000 liver failure patients who join the country’s wait list annually, less than 3% get an organ. Also, of the two lakh fresh annual registrations for kidneys, 8,000 manage a transplant. Thousands waiting for heart or lungs face bigger odds as barely 1% get an organ before time runs out.
Despite cadaveric organ donations witnessing a near fourfold increase in the last five years, the demand-supply disparity in the country remains grave.Over 2.5 lakh deaths in India are attributed to organ failure annually, while cadaver donations are still very few in comparison. India’s organ donation rate in 2016 stood at an abysmal 0.8 persons per million population compared to Spain’s 36 per million, Croatia’s 32 per million or US’s 26 per million.
Experts say the gap exists because only ten states and two UTs have an active donation and transplant programme.States such as UP , Chhattisgarh, Himachal Pradesh, Goa and the North-East are yet to make a debut. Stakeholders blame lack of awareness, infra and political will as well as myths and misconceptions for the sluggish pace of cadaver donation.
” Even after decades, the programme is a non-starter because of systemic complexities.The problem lies within hospitals and is not so much about people’s acceptance any more. Police formalities remain difficult and time-consuming, discouraging people from donating,” says Dr Sunil Shroff of Chennaibased Mohan Foundation. “
There have been cases where people have approached us wanting to donate organs but either the hospital or the city lacked the infrastructure to retrieve organs,” he says, underlining how in a country with an acute shortage, organs get wasted.
Tamil Nadu, Maharashtra, Kerala, Karnataka, Telengana and Gujarat currently lead the way. Delhi and Chandigarh too managed 30 donations in 2016.
Dr Vimal Bhandari, director of the National Organ and Tissue Transplant Organisation, says the government is aware of the crisis. “We have signed an MoU with Spain which has the world’s highest donation rate. About 100 countries are learning their model. Their experts will train five of our regional coordination centres,” he says, adding that Spain took 30 years to build its programme.Unlike Spain, where majority of brain deaths occur due to haemorrhage, in India, road accidents are the main killer.
India’s infrastructure too is growing. The national network facilitated 136 instances of organ sharing between cities and e states. “Last year, we even saved the lives of two foreigners who underwent heart transplants here,” Dr Bhandari says.e Tamil Nadu runs India’s g most successful programme by e taking a slew of decisions to ea se donations about a decade , back; families donating organs a don’t have to move for NOCs or post-mortems. Also, the state offers free kidney , liver and heart transplants in government hospitals like developed nations.
Maharashtra, that crossed 100 cadaver donations last year despite one of Mumbai ‘s top hospitals being involved in a kid ney racket, has carried out 1,064 transplants in the last five years. Pune has suddenly emerged as a high-donation centre, surpassing Mumbai. “Till April 2017, 69 donations took place in Maharashtra,” said Dr Gauri Rathod, Maharashtra’s nodal officer for organ donation.
Hyderabad and other districts of Telangana have crossed over 1,000 organ donations since 2013. From less than 1 per million population, the donation rate has now reached 4.4.From just 41 being recorded in 2013 to 106 organ donations in 2016. In 2017, over 80 organ donations have already been reported. “But there is an urgent need for education among doctors. In many cases, doctors are uncomfortable in declaring brain death. This is true of government hospitals,” says Dr G Swarnalatha, in-charge Jeevandan.
Karnataka, too, is charting its own success story with donations taking a leap from 18 in 2013 to 70 in 2016. Dr Kishore Phadke, convener at Jeevasarthakathe–the state organ transplant authority–attributes this to linked Aadhaar cards with pledging organs. ” Anyone who enrols for Aadhaar will be directed to the website of Jeevasarthakathe where they can pledge organs,” he says.
However, many states face unique problems. Consider Kerala which has recorded only 11 donations after 73 in 2016. “A doctor filed a PIL in the high court alleging hospitals are falsely declaring brain deaths to procure organs. It led to negative propaganda in the social media.Even government authorities didn’t stand by the transplant doctors,” says Dr Jose Chacko Periappuram of Lisie Hospital in Kochi. Kerala, however, has to its credit some of the unique organ transplants that include larynx, pancreas, small intestine and hand transplants.
Eastern India is the worst, with most states not having conducted cadaver donations at all.Only seven cadaver donations, including five in 2016, took place in West Bengal since 2012. According to Aditi Kishore Sarkar, state’s nodal officer for cadaver donation, “The drive to popularize organ donation through donor card distribution has failed.In 2017, there has not been a single cadaver organ transplant so far.” The state plans to introduce new laws to improve brain death screening.
Even states like Karnataka show a unhealthy skew . As Dr H Sudarshan Ballal, senior nephrologist and chairman at Manipal Hospitals, Bengaluru, says, “Of more than 300 transplants conducted by private hospitals, only 20% are cadaver organ transplants.” He says India needs more retrieval centres. “India’s largest centre of neuroscience, NIMHANS, is still not recognized as a retrieval centre.”
Source: http://timesofindia.indiatimes.com/life-style/health-fitness/health-news/organ-donation-up-4-fold-in-india-but-still-a-long-way-to-go/articleshow/59861347.cms
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New discovery may ‘impact treatment of autoimmune diseases’
Scientists have found a way of “dictating” cell fate to ensure controlled production of helper and regulatory T cells.
A new study has found a way of manipulating the differentiation of T cells in the immune system so as to strike a balance between pro-inflammatory and anti-inflammatory cells. This discovery may have implications for treating autoimmune diseases and some types of cancer.
Autoimmune diseases are triggered when our immune system misidentifies healthy cells as foreign bodies and decides to attack them. In this process, certain cells called “T cells,” which are found in the immune system, are involved.
T cells are of different types and have distinct functions, but their main role is to mediate immune reactions in the body. Some T cells are pro-inflammatory, promoting an immune response, while others are immunosuppressive, regulating the “aggressiveness” of this response.
Autoimmune diseases, as well as some types of cancer such as colorectal cancer and lung cancer, are mediated by certain T cell imbalances in the immune system. These imbalances lead either to anomalous inflammations, or to a lack of reaction, wherein the body is unable to identify pathogens.
Recently, much research has been conducted into a particular type of T cells called “T helper 17” (Th17) cells. Studies have found that Th17 cells can be unstable, thus sustaining autoimmune diseases and mediating some cancers.
A new study led by Dr. Sheng Ding, from the Gladstone Institutes in San Francisco, CA, discovered a way of changing cell fate to determine differentiation either into Th17 cells, which are pro-inflammatory, or into regulatory T cells, which are immunosuppressive.
The researchers published their findings in the journal Nature.
“Our findings could have a significant impact on the treatment of autoimmune diseases, as well as on stem cell and immuno-oncology therapies,” says Dr. Ding.
Chemical compound key to cell manipulation
In this study, experiments were conducted both in vitro (using cell cultures) and in vivo (using mice) to test the effect of a chemical compound called “(aminooxy)acetic acid” (AOA).
The researchers found that AOA is key in “telling” a progenitor cell to specialize into either Th17 or regulatory T cells. This allows for the formation of strategies to help promote cellular balance within the immune system.
Dr. Ding and his colleagues explain that this discovery can have wider implications for cancer and autoimmune disease treatments.
Determining differentiation into regulatory T cells rather than Th17 in the case of autoimmune diseases, for instance, could inhibit the exacerbated inflammatory effect caused by the helper cells.
The researchers are also eager to investigate any potential benefits this strategy might bring to stem cell-driven therapy; regulatory T cells can sometimes be used to prevent the system from rejecting organ transplants.
Dr. Ding and his colleagues now suggest that production of regulatory T cells might also be used to promote immune tolerance of cell transplants. They have also expressed their hope that the same strategy might prove effective – albeit indirectly – in cancer therapy.
“Our work could also contribute to ongoing efforts in immuno-oncology and the treatment of cancer. This type of therapy doesn’t target the cancer directly, but rather works on activating the immune system so it can recognize cancer cells and attack them.” – First author Dr. Tao Xu, Gladstone Institutes
While there is still some way to go in understanding how AOA might best be utilized to make treatments more effective, the researchers suggest that this is the first step in regaining control of faulty immune system mechanisms.
Source: http://www.medicalnewstoday.com/articles/318824.php
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At last, first cancer ‘living drug’ gets go-ahead
The US has approved the first treatment to redesign a patient’s own immune system so it attacks cancer.
The regulator – the US Food and Drug Administration – said its decision was a “historic” moment and medicine was now “entering a new frontier”.
The company Novartis is charging $475,000 (£367,000) for the “living drug” therapy, which leaves 83% of people free of a type of blood cancer.
Doctors in the UK said the announcement was an exciting step forward.
The living drug is tailor-made to each patient, unlike conventional therapies such as surgery or chemotherapy.It is called CAR-T and is made by extracting white blood cells from the patient’s blood.
The cells are then genetically reprogrammed to seek out and kill cancer.
The cancer-killers are then put back inside the patient and once they find their target they multiply.
‘Enormously exciting’
Dr Scott Gottlieb, from the FDA, said: “We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer.
“New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses.”
The therapy, which will be marketed as Kymriah, works against acute lymphoblastic leukaemia.
Most patients respond to normal therapy and Kymriah has been approved for when those treatments fail.
Dr Stephan Grupp, who treated the first child with CAR-T at the Children’s Hospital of Philadelphia, said the new approach was “enormously exciting”.
“We’ve never seen anything like this before,” he added.
That first patient had been near to death, but has now been cancer-free for more than five years.
Out of 63 patients treated with CAR-T therapy, 83% were in complete remission within three months and long-term data is still being collected.
However, the therapy is not without risks.
It can cause potentially life-threatening cytokine release syndrome from the rapid proliferation of the CAR-T cells in the body. This can be controlled with drugs.
New era
But the potential of CAR-T technology goes beyond one type of cancer.
Dr David Maloney, medical director of cellular immunotherapy at the Fred Hutchinson Cancer Research Center, said the FDA’s decision was a “milestone”.
He added: “We believe this is just the first of what will soon be many new immunotherapy-based treatments for a variety of cancers.
CAR-T technology has shown most promise against different blood-based cancers.
However, it has struggled against “solid tumours” such as lung cancer or melanoma.
Dr Prakash Satwani, a paediatric oncologist at Columbia University Medical, said: “The results haven’t been that great when you compare it with acute lymphoblastic leukaemia, but I’m sure the technology will get better in the near future.”
Boosting the immune system is already a cornerstone of modern cancer treatment.
A range of drugs that “take the brakes off” the immune system to allow it to attack cancer more freely have already been adopted around the world.
CAR-T technology, which goes a step further and redesigns the immune system, is at a much earlier stage. Prof Peter Johnson, the chief clinician at the charity Cancer Research UK, said: “The first genetically modified cell therapy to be approved by the FDA is an exciting step forward.
“We still have a lot to learn about how to use it safely and who might benefit from it, so it is important to recognise this is just a first step.”
Source: http://www.bbc.com/news/health-41094990
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Researchers discover MRI can measure kidney scarring and predict future kidney function
Researchers from St. Michael’s Hospital have made what are believed to be two world first discoveries: an MRI can measure kidney damage and can predict future kidney function within one year while avoiding needle biopsies.
The researchers used a specific magnetic resonance imaging test called an elastogram to measure kidney scarring in 17 people who had kidney transplants, according to the study published online in the Clinical Journal of the American Society of Nephrology.
An elastogram maps the stiffness of tissue using MRI to determine the presence of scarring, according to Dr. Anish Kirpalani, the study’s lead author, a radiologist and a scientist in the Li Ka Shing Knowledge Institute of St. Michael’s.
Scarring is a major cause of kidney transplant failure.
“Healthy kidney is soft, whereas scar tissue is stiffer,” said Dr. Darren Yuen, a transplant nephrologist and scientist in the Keenan Research Centre for Biomedical Science of St. Michael’s.
“We needed a way to measure how soft or stiff your kidney is without actually going inside the body. Using the MRI elastogram, we were able to measure kidney stiffness, which gave us an indication of how much scarring there was.”
Scarring is irreversible and can cause progressive kidney injury that can eventually lead to kidney failure. Diabetes, high blood pressure and kidney transplant rejection all cause scarring.
Needle biopsy is the current “gold standard” way to assess kidney scarring. A long needle is inserted into the kidney and a sample about the size of a mechanical pencil tip is removed. The procedure requires pain medications, can be associated with bleeding and requires a day off of work, according to the authors.
The study found that the MRI results were not only comparable to the results of a kidney biopsy, but the test was able to detect a high variability in the amount and location of scarring throughout the entire organ.
“The MRI allowed us to get a full picture of the kidney, whereas with a biopsy we would only see a tiny piece,” said Dr. Kirpalani.
“We were able to tell that in some parts of the kidney it’s very stiff, and in others, it’s not stiff at all, which is information we couldn’t get from a biopsy.”
The researchers also found that kidney stiffness predicted how well the kidney would be working one year after the MRI. They found that those with higher levels of stiffness in their kidneys had a greater loss of kidney function, while those with softer kidneys did not.
This shows that MRI can accurately predict future kidney function, according to the authors, which may be particularly helpful for kidney transplant patients.
“When we’re looking at a transplanted kidney, we’re dealing with a precious resource–these patients have waited a long time for a transplant, and have been on dialysis, which is a difficult and painful process,” said Dr. Kirpalani.
“Scarring is a big problem for transplant patients, and with MRI we may be able to better guide how kidney transplant patients are treated early on to improve their long-term outcomes.”
MRIs would not replace biopsies, said Dr. Yuen, but rather act as an additional test to give a more comprehensive understanding of kidney health.
“Clinicians are hesitant to send patients for a test that has risks such as internal bleeding unless a diagnosis can’t be made without it,” he said. “With this new MRI test, doctors can gather valuable information in the many patients for whom the risks of a biopsy are too high.”
He also emphasized that this new MRI test may help facilitate the testing of new anti-scarring treatments.
“There are currently no anti-scarring drugs on the market, in part because it is hard to rationalize doing multiple kidney biopsies as part of a pharmaceutical trial,” said Dr. Yuen.
“By providing a needle-free way to measure kidney scarring, we may create more opportunities for this crucial research into finding an effective anti-scarring treatment.”
The study was conducted in the hospital’s MRI research centre, which houses MRI equipment dedicated specifically to clinical research.
“The unique MRI research centre that we have created, including elastography equipment, is focused on research that will directly impact patient care, allowing us to do this important study in people with transplant kidneys,” said Dr. Kirpalani.
Source: http://www.medicalnewstoday.com/releases/319278.php
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