Irregular heartbeat linked to higher thyroid hormone levels

 Individuals with higher levels of thyroid hormone (free thyroxine, FT4) circulating in the blood were more likely than individuals with lower levels to develop irregular heartbeat, or atrial fibrillation, even when the levels were within normal range, according to new research in the American Heart Association’s journal Circulation.

“Our findings suggest that levels of the thyroid hormone, free thyroxine, circulating in the blood might be an additional risk factor for atrial fibrillation,” said study lead author Christine Baumgartner, M.D., specialist in General Internal Medicine from the University Hospital of Bern, Switzerland, and currently a postdoctoral scholar at University of California San Francisco. “Free thyroxine hormone levels might help to identify individuals at higher risk.”

In the United States, irregular heartbeat (atrial fibrillation) affects between 2.7 to 6.1 million people and is estimated to affect up to 12.1 million people by 2030. It occurs when the two upper chambers of the heart, called the atria, beat irregularly and faster than normal. Symptoms may include heart palpitations, dizziness, sweating, chest pain, anxiety, fatigue during exertion and fainting, but sometimes patients with atrial fibrillation have no symptoms at all. Although people can live with irregular heartbeat, it can cause chronic fatigue and increase the risk of serious illnesses, such as stroke and heart failure, potentially associated with lifelong disability and even death. Fortunately, medication and other therapies are available to treat irregular heartbeat and reduce the risk of the associated symptoms and complications.

The thyroid gland is a small gland in the neck. In response to thyroid-stimulating hormone released by the pituitary gland, the thyroid gland secretes thyroid hormones required to regulate energy metabolism. Patients with low levels of thyroid hormone, or hypothyroidism, may require medications containing thyroid hormone (thyroxine) to increase their hormonal levels. Sometimes intake of thyroxine sometimes can increase these levels too much.

Previous studies showed that the risk of irregular heartbeat is greater among individuals who produce too much thyroid hormone than among those with normal hormonal levels. What was unclear, however, was whether levels that were high but still within the normal range could also increase the risk of irregular heartbeat.

To understand this relationship, investigators looked at the occurrence of irregular heartbeat among individuals with thyroid hormone levels that were still within normal range. They found that individuals with higher blood levels of FT4 within the normal range at the beginning of the study were significantly more likely than those with lower levels to subsequently develop irregular heartbeat.

When separated into four equal-sized groups, the group with the highest FT4 levels had a 45 percent increased risk of irregular heartbeat, compared to the group with the lowest levels. Even more modest increases in thyroid hormone were associated with an increased risk. Among individuals with the second highest levels, the risk was 17 percent greater, and among those with the third highest levels the risk was 25 percent greater, compared to those with the lowest levels. High levels of thyroid-stimulating hormone (TSH) within the normal range, however, were not associated with an increased risk of atrial fibrillation.

“Patients who are treated with thyroxine, one of the most frequently prescribed drugs in the United States, generally have higher circulating free thyroxine levels compared to untreated individuals,” Baumgartner said. “So, an important next step is to see whether our results also apply to these patients, in order to assess whether target free thyroxine thyroid hormone concentrations for thyroid-replacement therapy need to be modified.”

The investigators analyzed data from 11 studies from Europe, Australia, and the United States that measured thyroid function and the occurrence of irregular heartbeat. Overall, the studies included 30,085 individuals. Their average age was 69 years, and slightly more than half were women. On average, follow-up ranged from 1.3 to 17 years. The investigators obtained the studies by searching the MEDLINE and EMBASE medical databases through July 2016.

Asthma medication may have psychiatric side effects

In a Pharmacology Research & Perspectives study, the asthma medication montelukast (trade name Singulair) was linked with neuropsychiatric reactions such as depression and aggression, with nightmares being especially frequent in children.

For the study, investigators examined all adverse drug reactions on montelukast in children and adults reported to the Netherlands Pharmacovigilance Center Lareb and the WHO Global database, VigiBase®, until 2016.

“Because of the high incidence of neuropsychiatric symptoms–especially nightmares–after using montelukast in both children and adults, the clinician should discuss the possibility of these adverse events with the patient and parents,” said Meindina Haarman, lead author of the study.

Using DNA to predict schizophrenia and autism

Huntington’s disease, cystic fibrosis, and muscular dystrophy are all diseases that can be traced to a single mutation. Diagnosis in asymptomatic patient for these diseases is relatively easy – You have the mutation? Then you are at risk. Complex diseases, on the other hand, do not have a clear mutational footprint. A new multi-institutional study by Japanese researchers shows a potential rare gene mutation that could act as a predictor for two neurodevelopmental disorders, schizophrenia and autism.

“Aberrant synapse formation is important in the pathogenesis of schizophrenia and autism,” says Osaka University Professor Toshihide Yamashita, one of the authors of the study. “Microglia contribute to the structure and function of synapse connectivities.”

Microglia are the only cells in the brain that express the receptor CX3CR1. Mutations in this receptor are known to affect synapse connectivity and cause abnormal social behavior in mice. They have also been associated with neuroinflammatory diseases such as multiple sclerosis, but no study has shown a role in neurodevelopment disorders.

Working with this hypothesis, the researchers conducted a statistical analysis of the CX3CR1 gene in over 7000 schizophrenia and autism patients and healthy subjects, finding one mutant candidate, a single amino acid switch from alanine to threonine, as a candidate marker for prediction.

“Rare variants alter gene function but occur at low frequency in a population. They are of high interest for the study of complex diseases that have no clear mutational cause,” said Yamashita, who added the alanine threonine substitution was a rare variant.

The structure of CX3CR1 includes a domain known as Helix 8, which is important for initiating a signaling cascade. Computer models showed that one amino acid change is enough to compromise the signaling.

“The variant changes the region from hydrophobic to hydrophilic and destabilize Helix 8. We overexpressed the mutation in cells and found Akt signaling was disrupted,” explains Yamashita.

According to Yamashita, the findings are the first to connect a genetic variation in microglia with neurodevelopment disorders. Moreover, he hopes that the discovery could become a basis for predictive diagnostics.

“There is no reliable way to diagnose schizophrenia or autism in asymptomatic patients. Deeper understanding of the genetic risk factors will help us develop preventative measures.”

Stabilizing TREM2 — a potential strategy to combat Alzheimer’s disease

A gene called triggering receptor expressed on myeloid cells 2, or TREM2, has been associated with numerous neurodegenerative diseases, such as Alzheimer’s disease, Frontotemporal lobar degeneration, Parkinson’s disease, and Nasu-Hakola disease. Recently, a rare mutation in the gene has been shown to increase the risk for developing Alzheimer’s disease.

Independently from each other, two research groups have now revealed the molecular mechanism behind this mutation. Their research, published today in EMBO Molecular Medicine, sheds light on the role of TREM2 in normal brain function and suggests a new therapeutic target in Alzheimer’s disease treatment.

Alzheimer’s disease, just like other neurodegenerative diseases, is characterized by the accumulation of specific protein aggregates in the brain. Specialized brain immune cells called microglia strive to counter this process by engulfing the toxic buildup. But as the brain ages, microglia eventually lose out and fail to rid all the damaging material.

TREM2 is active on microglia and enables them to carry out their protective function. The protein spans the microglia cell membrane and uses its external region to detect dying cells or lipids associated with toxic protein aggregates. Subsequently, TREM2 is cut in two. The external part is shed from the protein and released, while the remaining part still present in the cell membrane is degraded. To better understand TREM2 function, the two research groups took a closer look at its cleavage. They were led by Christian Haass at the German Center for Neurodegenerative Diseases at the Ludwig-Maximilians-University in Munich, Germany, and Damian Crowther of AstraZeneca’s IMED Neuroscience group in Cambridge, UK together with colleagues at the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto and the Cambridge Institute for Medical Research, University of Cambridge, UK.

Using different technological approaches, both groups first determined the exact site of protein shedding and found it to be at amino acid 157. Amino acid 157 was no unknown. Only recently, researchers from China had uncovered that a mutation at this exact position, referred to as p.H157Y, increased the risk of Alzheimer’s disease. Together, these observations indicate that protein cleavage is perturbed in the p.H157 mutant and that this alteration promotes disease development.

As a next step, Haass and Crowther’s groups investigated the biochemical properties of the p.H157Y mutant protein more closely. They found that the mutant was cleaved more rapidly than a healthy version of the protein. “Our results provide a detailed molecular mechanism for how this rare mutation alters the function of TREM2 and hence facilitates the progression of Alzheimer’s disease,” said Crowther.

While most TREM2 mutations affect protein production, the mechanism behind p.H157Y is somewhat different. The p.H157Y mutation allows the protein to be correctly manufactured and transported to the microglia cell surface, but then it is cleaved too quickly. “The end result is the same. In both cases, there is too little full-length TREM protein on microglia,” said Haass. “This suggests that stabilizing TREM2, by making it less susceptible to cleavage, may be a viable therapeutic strategy.”

Repairing damaged hearts with self-healing heart cells

New research has discovered a potential means to trigger damaged heart cells to self-heal. The discovery could lead to groundbreaking forms of treatment for heart diseases. For the first time, researchers have identified a long non-coding ribonucleic acid (ncRNA) that regulates genes controlling the ability of heart cells to undergo repair or regeneration. This novel RNA, which researchers have named “Singheart”, may be targeted for treating heart failure in the future. The discovery was made jointly by A*STAR’s Genome Institute of Singapore (GIS) and the National University Health System (NUHS), and is now published in Nature Communications.

Unlike most other cells in the human body, heart cells do not have the ability to self-repair or regenerate effectively, making heart attack and heart failure severe and debilitating. Cardiovascular disease (CVD) is the leading cause of death worldwide, with an estimated 17.7 million people dying from CVD in 2015 (1). CVD also accounted for close to 30% of all deaths in Singapore in 2015 (2).

In this project, the researchers used single cell technology to explore gene expression patterns in healthy and diseased hearts. The team discovered that a unique subpopulation of heart cells in diseased hearts activate gene programmes related to heart cell division, uncovering the gene expression heterogeneity of diseased heart cells for the first time. In addition, they also found the “brakes” that prevent heart cells from dividing and thus self-healing. Targeting these “brakes” could help trigger the repair and regeneration of heart cells.

“There has always been a suspicion that the heart holds the key to its own healing, regenerative and repair capability. But that ability seems to become blocked as soon as the heart is past its developmental stage. Our findings point to this potential block that when lifted, may allow the heart to heal itself,” explained A/Prof Roger Foo, the study’s lead author, who is Principal Investigator at both GIS and NUHS’ Cardiovascular Research Institute (CVRI) and Senior Consultant at the National University Heart Centre, Singapore (NUHCS).

“In contrast to a skin wound where the scab falls off and new skin grows over, the heart lacks such a capability to self-heal, and suffers a permanent scar instead. If the heart can be motivated to heal like the skin, consequences of a heart attack would be banished forever,” added A/Prof Foo.

The study was driven by first author and former Senior Research Fellow at the GIS, Dr Kelvin See, who is currently a Postdoctoral Researcher and Mack Technology Fellow at University of Pennsylvania.

“This new research is a significant step towards unlocking the heart’s full regenerative potential, and may eventually translate to more effective treatment for heart diseases. Heart disease is the top disease burden in Singapore and strong funding remains urgently needed to enable similar groundbreaking discoveries,” said Prof Mark Richards, Director of CVRI.

Executive Director of GIS, Prof Ng Huck Hui added, “This cross-institutional research effort serves as a strong foundation for future heart studies. More importantly, uncovering barriers that stand in the way of heart cells’ self-healing process brings us another step closer to finding a cure for one of the world’s biggest killers.”

Skewing the aim of targeted cancer therapies

Headlines, of late, have touted the successes of targeted gene-based cancer therapies, such as immunotherapies, but, unfortunately, also their failures.

Broad inadequacies in a widespread biological concept that affects cancer research could be significantly deflecting the aim of such targeted drugs, according to a new study. A team exploring genetic mechanisms in cancer at the Georgia Institute of Technology has found evidence that a prevailing concept about how cells produce protein molecules, particularly when applied to cancer, could be erroneous as much as two-thirds of the time.

Prior studies by other researchers have also critiqued this concept about the pathway leading from genetic code to proteins, but this new study, led by cancer researcher John McDonald, has employed rare analytical technology to explore it in unparalleled detail. The study also turned up novel evidence for regulating mechanisms that could account for the prevailing concept’s apparent shortcomings.

RNA concept incomplete

The concept stems from common knowledge about the assembly line inside cells that starts with code in DNA, is transcribed to messenger RNA, then translated into protein molecules, the cell’s building blocks.

That model seems to have left the impression that cellular protein production works analogously to an old-style factory production line: That the amount of a messenger RNA encoded by DNA on the front end translates directly into the amount of a corresponding protein produced on the back end. That idea is at the core of how gene-based cancer drug developers choose their targets.

To put that assumed congruence between RNA production and protein production to the test, the researchers examined — in ovarian cancer cells donated by a patient — 4,436 genes, their subsequently transcribed messenger RNA, and the resulting proteins. The assumption, that proverbial factory orders passed down the DNA-RNA line determine in a straightforward manner the amount of a protein being produced, proved incorrect 62 percent of the time.

RNA skews drug cues

“The messenger RNA-protein connection is important because proteins are usually the targets of gene-based cancer therapies,” McDonald said. “And drug developers typically measure messenger RNA levels thinking they will tell them what the protein levels are.” But the significant variations in ratios of messenger RNA to protein that the researchers found make the common method of targeting proteins via RNA seem much less than optimal.

McDonald, Mengnan Zhang and Ronghu Wu published their results on August 15, 2017 in the journal Scientific Reports. The work was funded by the Ovarian Cancer Institute, The Deborah Nash Endowment, Atlanta’s Northside Hospital and the National Science Foundation. The spectrophotometric technology needed to closely identify a high number of proteins is rare and costly but is available in Wu’s lab at Georgia Tech.

Whereas many studies look at normal tissue versus cancerous tissue, this new study focused on cancer progression, or metastasis, which is what usually makes cancer deadly. The researchers looked at primary tumor tissue and also metastatic tissue.

Hiding drug targets

“The idea that any change in RNA level in cancerous development flows all the way up to the protein level could be leading to drug targeting errors,” said McDonald, who heads Georgia Tech’s Integrated Cancer Research Center. Drug developers often look for oddly high messenger RNA levels in a cancer then go after what they believe must be the resulting oddly high levels of a corresponding protein.

Taking messenger RNA as a protein level indicator could actually work some of the time. In the McDonald team’s latest experiment, in 38 percent of the cases, the rise of RNA levels in cancerous cells did indeed reflect a comparable rise of protein levels. But in the rest of cases, they did not.

“So, there are going to be many instances where if you’re predicting what to give therapeutically to a patient based on RNA, your prescription could easily be incorrect,” McDonald said. “Drug developers could be aiming at targets that aren’t there and also not shooting for targets that are there.”

RNA muted or magnified

The analogy of a factory producing building materials can help illustrate what goes wrong in a cancerous cell, and also help describe the study’s new insights into protein production. To complete the metaphor: The materials produced are used in the construction of the factory’s own building, that is, the cell’s own structures.

In cancer cells, a mutation makes protein production go awry usually not by deforming proteins but by overproducing them. “A lot of mutations in cancer are mutations in production levels. The proteins are being overexpressed,” said McDonald, who is also a professor in Georgia Tech’s School of Biological Sciences.

A bad factory order can lead to the production of too much of a good material and then force it into the structures of the cell, distorting it. The question is: Where in the production line do bad factory orders appear?

According to the new study, the answer is less straightforward than perhaps previously thought.

Micro RNA managing

The orders don’t all appear on the front end of the assembly line with DNA over-transcribing messenger RNA. Additionally, some mutations that do over-transcribe messenger RNA on the front end are tamped down or canceled by regulating mechanisms further down the line, and may never end up boosting protein levels on the back end.

Regulating mechanisms also appear to be making other messenger RNA, transcribed in normal amounts, unexpectedly crank out inordinate levels of proteins.

At the heart of those regulating systems, another RNA called micro RNA may be micromanaging how much, or little, of a protein is actually produced in the end.

“We have evidence that micro RNAs may be responsible for the non-correlation between the proteins and the RNA, and that’s completely novel,” McDonald said. “It’s an emerging area of research.”

Micro RNA, or miRNA, is an extremely short strand of RNA.

No one at fault

McDonald would like to see tissues from more cancer patients undergo similar testing. “Right now, with just one patient, the data is limited, but I also really think it shows that the phenomenon is real,” McDonald said.

“Many past studies have looked at one particular protein and a particular gene, or a particular handful. We looked at more than 4,000,” McDonald said. “What that brings up is that the phenomenon is probably not isolated but instead genome-wide.”

The study’s authors would also like to see rarely accessible, advanced protein detecting technology become more widely available to biomolecular researchers, especially in the field of cancer drug development. “Targeted gene therapy is a good idea, but you need the full knowledge of whether it’s affecting the protein level,” McDonald said.

He pointed out that no one is at fault for the possible incompleteness of commonly held concepts about protein production.

As science progresses, it naturally illuminates new details, and formerly useful ideas need updating. With the existence of new technologies, it may be time to flesh out this particular concept for the sake of cancer research progress.

A new HER2 mutation, a clinical trial and a promising diagnostic tool for metastatic breast cancer

There is a group of metastatic breast cancers that has the HER2 gene amplified – the cells have many copies of it – which leads to enhanced activity of the product enzyme, a tyrosine kinase. HER2 has been established as a therapeutic target in breast cancer, and breast cancers in which the HER2 gene is not amplified do not, in general, respond to HER2-directed therapeutic approaches.

A few years ago, when the research teams of Dr. Matthew Ellis and others carried out a molecular characterization of breast cancer tumors, they found a new mutation in HER2 that was different from gene amplification but also resulted in tyrosine kinase being constantly activated.

“In this particular activation mechanism, the cells develop a subtle mutation within the functional part of the HER2 gene that activates the enzyme,” said Ellis, professor and director of the Lester and Sue Smith Breast Center, part of the National Cancer Institute-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine. “The mutation locks the enzyme into an ‘on’ position.”

Ellis and his colleagues developed a preclinical model to study this new HER2 mutation and discovered that the enhanced enzymatic activity could trigger tumor formation. Furthermore, these tumor cells were sensitive to an experimental drug, neratinib. With this information in hand, the researchers took the next step.

“We launched a phase II clinical trial of neratinib in patients with metastatic breast cancer carrying a HER2 mutation,” Ellis said. “Finding patients that are positive for a HER2 mutation required a national collaboration because we had to screen hundreds of patients to identify the 2 to 3 percent that have a tumor driven by a HER2 mutation. The results of the clinical trial were encouraging in that about 30 percent of the 16 patients treated with neratinib had a meaningful clinical response showing significant disease stabilization or regression. Neratinib was well tolerated by most patients.”

“This is the first time we had a reasonable number of patients treated for HER2 mutations in whom we could estimate the response rate.”

The number of patients who could potentially benefit from this new treatment approach is estimated to be in the thousands. The researchers estimate that as many as 200,000 patients are likely to be living with metastatic breast cancer today in the United States. Based on the estimate that the new mutation is present in 2 to 3 percent of cases, the researchers calculated that approximately 4,000 to 6,000 patients with metastatic breast cancer carry a HER2 mutation and are therefore potential candidates for neratinib treatment.

Circulating tumor DNA analysis, a promising diagnostic tool

To identify the patients in this study who carried the new HER2 mutation, the researchers required tissue from the tumor, a biopsy, from which they could extract and sequence the genetic material to determine the presence of the HER2 mutation. This task turned out to be a major challenge because for 20 to 30 percent of the patients the researchers did not have sufficient material to make the diagnosis.

“To assist in our ability to identify patients with HER2 mutation-positive tumors, we conducted circulating tumor DNA analysis,” Ellis said. “The tumor’s DNA is released into the human bloodstream, and we were able to determine the presence of the mutation in blood samples from the patients. Importantly the circulating tumor DNA results were highly concordant with the tumor sequencing results, and they were much easier to determine. Notably, the blood test was sensitive enough that we could use it as a tool to determine eligibility for the clinical trial.”

In addition to bringing to the table a novel treatment for metastatic breast cancer carrying a HER2 mutation, the researchers have tested the value of the circulating tumor DNA as a disease-monitoring marker.

“A circulating tumor DNA-based blood test also could therefore be potentially used to monitor tumor progression and to determine whether patients are responding or not to treatment after just one month of therapy,” Ellis said.

Ellis also is a McNair Scholar at Baylor.

Read all the details of this study, the full list of contributors and their financial support in Clinical Cancer Research.

Towards a safe and scalable cell therapy for type 1 diabetes by simplifying beta cell differentiation

More than 36 million people globally are affected by type 1 diabetes (T1D), a lifelong disorder where insulin producing cells are attacked and destroyed by the immune system resulting in deficient insulin production that requires daily blood glucose monitoring and administration of insulin. While successful outcomes from islet transplantations have been reported, very few patients can benefit from this therapeutic option due to limited access to cadaveric donor islets. Human pluripotent stem cell (hPSCs) could offer an unlimited and invariable source of insulin-producing beta cells for treatments of a larger population of T1D patients.

With the vision of providing a cell therapy for type 1 diabetes patients, scientists at the University of Copenhagen have identified a unique cell surface protein present on human pancreatic precursor cells providing for the first time a molecular handle to purify the cells whose fate is to become cells of the pancreas – including insulin producing cells. The work, outlined in a landmark study entitled ‘Efficient generation of glucose-responsive beta cells from isolated GP2+ human pancreatic progenitors’ has just been published in Cell Reports and is available here.

A biomarker to clearly separate cell populations is a holy grail of cell therapy research for the reasons of safety and end product consistency. By using this cell surface marker, the researchers have engineered a streamlined and simplified differentiation process to generate insulin-producing cells for future treatment of type 1 diabetes patients. The process enables cost-efficient manufacturing and exploits at its core an intermediate cell bank of purified pancreatic precursor cells.

The discovery of the new marker has also enabled the researchers to streamline and refine the process of producing hPSC-derived insulin cells.

“By starting with a purified population of pancreatic precursor cells instead of immature stem cells we eliminate the risk of having unwanted tumorigenic cells in the final cell preparation and thus generate a safer cell product for therapeutic purposes”, explains Assistant Professor Jacqueline Ameri, first author on the paper.

Professor Henrik Semb, Managing Director of the Danish stem cell centre (DanStem) explains:

“Although significant progress has been made towards making insulin producing beta cells in vitro (in the lab), we are still exploring how to mass-produce mature beta cells to meet the future clinical needs. Our current study contributes with valuable knowledge on how to address key technical challenges such as safety, purity and cost-effective manufacturing, aspects that if not confronted early on, could hinder stem cell therapy from becoming a clinically and commercially viable treatment in diabetes.”

Indeed, Semb’s group is among the first to directly address not only the therapeutic concept but to incorporate very early the manufacturing considerations in their process to ensure that future commercialization will be possible.

To translate the current findings into a potential treatment of type 1 diabetes, Ameri and Semb aim to commercialize their recent patent pending innovations by establishing the spin out company PanCryos. PanCryos has assembled a team with experts in stem cell biology, islet transplantations, business and regulatory guidance and is currently funded by a KU POC grant and a pre-seed funding from Novo Seeds.

“In parallel with other groups in this field, we have been working on a cell therapy for type 1 diabetes for many years. What is unique about our approach is the simplification of our protocol which acknowledges that eventually the process will need to be scaled up for manufacturing. PanCryos is being established to ensure the development of the first scalable allogenic cell therapy for type 1 diabetes so we can offer the route to an affordable therapy by providing a product that will not be too expensive to produce, as has occurred too often in the developing cell therapy field”, explains Jacqueline Ameri, co-founder and CEO for PanCryos.

Cell mechanism discovery could lead to ‘fundamental’ change in leukaemia 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.

Better treatment for kidney cancer thanks to new mouse model

Roughly 2-3 percent of all people suffering from cancer have kidney cancer. The most common form of this disease is called clear cell renal cell carcinoma (ccRCC). In roughly half of all patients with this disease, the tumor develops metastases and generally cannot be cured.

New Mouse Model for Investigating Kidney Cancer

The research of different types of cancer and the testing of new treatments depends on accurate mouse models. This is because the tumors in mice mirror the genetics as well as the molecular and cellular properties of tumors in humans. Despite decades of effort, however, researchers were unable to develop a mouse model of renal cell carcinoma – until now. Scientists conducting a long-term research project at the University of Zurich were able to develop a mouse model. The study was led by Sabine Harlander and her colleagues at the Institute of Physiology of the University of Zurich in the lab of Professor Ian Frew, who has recently joined the University of Freiburg in Germany. The researchers began by identifying the genes that often mutate in human renal cell carcinomas. They then mutated three of these genes simultaneously in renal cells of mice, which then developed renal cancer.

Gene Mutations Promote Uncontrolled Cell Division

The progression from gene mutation in the renal cells to the development of a tumor took eight to twelve months. This lengthy period of time, compared to a mouse’s lifetime, indicates that additional factors play a role in tumor development. The researchers therefore decided to take a closer look at the protein-encoding genes in the mouse tumors. They discovered that in all of the tumors at least one of the many genes responsible for the correct functioning of the primary cilium had mutated. The primary cilium is a hair-like structure found on the cell’s surface and is responsible for coordinating cell signaling, among other things.

Based on this finding, the researchers found that similar mutations also occur in renal cell carcinomas in humans. The scientists now believe that the loss of normal function in the primary cilium leads to the uncontrollable division of renal epithelial cells, which contributes to the formation of ccRCC. “This research project is a prime example of how mouse models can help us to better understand cancer diseases in human beings,” says Sabine Harlander.

Mouse Model Enables Development of Better Treatments

The new mouse model will make it possible to develop better therapies for renal cancer. For example, in the case of patients with renal carcinoma metastasis who are given different medications, some patients respond to the medications, while others do not. The same phenomenon can be observed when mice with renal cancer are treated with the same drugs as the humans. Some tumors shrink, while others do not. Now researchers can investigate the factors that contribute to why certain tumours respond to certain medications and not to others. “We hope that our mouse model, which allows us to combine drug testing and genetic analysis, will provide a deeper understanding of why tumors are sensitive or resistant to drugs,” states Ian Frew. Such vital information could be used to better adjust treatments to the characteristics of each patient.

The mouse model could also contribute to the further development of immunotherapies – a method in which the body’s immune system is stimulated, so that it intensifies its fight against tumor cells. In the last few years, much progress has been made in this field of cancer research, also for the treatment of renal cell carcinomas. Now, thanks to the new mouse model, it will be possible to study how renal tumors are able to develop in an environment with a normal immune system, and how cancer cells manage to evade the immune system’s attacks. Ultimately, the researchers’ goal is to use these new findings to improve the effectiveness of immunomodulatory treatments.