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12th December 2019
Their study, which was done in collaboration with Professor Suresh Awale from the University of Toyama, Japan, shows that all three molecules kill pancreatic cancer cells in a petri dish. Two of these killed the cells more effectively than the original Grandifloracin molecule.
Whilst this research is more than five years away from trialling new drugs in humans, the researchers say these molecules could become a promising new class of drugs for treating pancreatic cancer.
The research is published in the journal ChemMedChem.
Dr Simon Lewis, Senior Lecturer in Chemistry from the University of Bath, said: “Pancreatic cancers are especially aggressive and fast-growing, so the tumours develop faster than the blood vessels can supply nutrients to them.
“This leads to a lack of nutrients, to an extent that would kill ordinary cells, but the pancreatic cancer cells can survive these ‘austere’ conditions and keep on growing.
“The molecules we have identified are so-called ‘anti-austerity’ agents that can remove the ability of the cancer cells to tolerate these starvation conditions, so they will die, whereas ordinary cells with a normal supply of nutrients remain unaffected.”
Dr Lorenzo Caggiano, Senior Lecturer in the Medicinal Chemistry group at the University’s Department of Pharmacy & Pharmacology, said: “Through evolution, nature has developed a huge variety of active compounds to help it survive and thrive under a wide range of environmental conditions.
“These so-called natural products are of great interest in the development of new drugs and as such approximately a quarter of all medicines are derived from plants.
“As part of our ongoing research into the development of new treatments for brain cancers based on compounds found in daffodils, the research published in collaboration with Dr Lewis describes a compound also found in flowering plants that is able to selectively kill pancreatic cancer cells in a new way.
“This exciting approach could potentially lead to a new drug to treat pancreatic cancers that is more effective yet less toxic than current treatments.”
Now Yale scientists have essentially flipped this script and found that when impaired a molecularly similar regulator can cause the damaging immune system attacks on skin and organs that are the hallmark of the autoimmune disease lupus, as reported in Science Translational Medicine.
The study results help explain the origins of lupus and suggest novel ways researchers might be able to restore function of this inhibitor and provide much needed new therapy to treat the disease, the scientists said.
Yale researchers found that mice lacking an immune system inhibitor called programmed death-1 homolog, or PD-1H, spontaneously developed symptoms that resemble two forms of lupus — systemic, in which the immune system attacks multiple organs; and cutaneous, which is marked by pronounced skin deformities.
“This molecule is clearly involved in inhibiting lupus, but it seems to be selective because it does not have the same effect in several other autoimmune diseases,” said senior author Lieping Chen, the United Technologies Corporation Professor in Cancer Research, and professor of immunobiology, dermatology, and medicine.
PD-1H is molecularly similar to the more commonly known PD-1 molecule, which also helps suppress immune system response. Chen was a pioneer in identifying and developing inhibitors to PD-1, which freed T cells to attack several forms of cancer. Several labs have also tried to use PD-1H as a cancer treatment but so far have been unsuccessful.
Chen said his findings suggest that in people with lupus the function of PD-1H is critical. When it is impaired, they are vulnerable to the immune system attacks on skin and multiple organs that are the hallmark of the disease.
Lupus patients currently have very limited options for treatment, but the new findings suggest a novel approach called protein fusion might mimic PD-1H and help control the immune system and combat the disease, Chen said.
5th December 2019
The study is the first to show the drug, tofacitinib (Xeljanz) has a direct effect on cells lining the gut by correcting defects that occur in inflammation. Until now, the effects of tofacitinib on intestinal epithelial cell functions were largely unknown.
“Our work increases our understanding of how this drug is useful for treating ulcerative colitis,” said Declan McCole, a professor of biomedical sciences in the UCR School of Medicine, and the lead author of the study that appears in the journal Inflammatory Bowel Diseases. “We now better understand where in the gut the drug is working, and how.”
McCole explained that increased intestinal permeability — or leakiness — is a feature of ulcerative colitis and plays a critical role in promoting inflammation. His team tested tofacitinib in human intestinal epithelial cell lines, as well as in organoids, or colonoids, that were derived from primary human colonic stem cells isolated from human subjects — primarily patients undergoing elective colonoscopy for colon cancer screening — and found tofacitinib repaired inflammation-induced permeability defects in both.
The epithelium is a thin layer that lines the alimentary canal. The gastrointestinal epithelium is comprised of cells that have gaps between them, making them selectively permeable and providing a barrier that keeps out pathogens, toxins, and antigens from entering the gut, while allowing the absorption of nutrients. In ulcerative colitis, this epithelial permeability becomes leaky, allowing bacterial products to cross into the gut and nutrients and water to leak out. This, in turn, triggers immune responses, resulting in fluid loss and diarrhea.
“We found tofacitinib fixes the leakiness in the intestinal barrier,” McCole said. “Specifically, it fixes intestinal epithelial permeability defects caused by ‘interferon-gamma,’ an inflammatory cytokine involved in autoimmune diseases such as ulcerative colitis and rheumatoid arthritis.”
“By targeting specific molecules, the drug inhibits a pathway that is activated by inflammation,” said Anica Sayoc-Becerra, a graduate student in the Biomedical Sciences Graduate Program, a member of McCole’s lab, and the first author of the research paper. “Our study shows tofacitinib is not just acting on immune cells, as was first thought, but can have a direct effect on the epithelial cells that are the key factor in maintaining gut barrier function.”
In the first study of its kind, researchers analysed almost 2700 IBD patients in a Paris referral centre to understand the respective roles of IBD activity and drugs in promoting systemic serious viral infection (SVI). The study identified clinically active IBD and thiopurines (a class of immunomodulators used to treat an estimated 60% of IBD patients2) as the main drivers of infection. Despite the highest risk of infection being seen in young patients between the ages of 18 and 35, a three-fold increased incidence of severe viral infections was observed in IBD patients of all ages.
The study also uncovered a concerning link between thiopurine use and a number of harmful infections. Whilst IBD patients receiving no treatment were at a similar risk level to the general population, patients treated with immunomodulators were found to be six times more likely to develop an SVI. The most common SVIs developed by IBD patients were identified as Epstein-Barr virus (EBV), which is associated with a range of diseases such as glandular fever and Hodgkin’s Lymphoma, and cytomegalovirus (CMV), an infection which can pose a risk to unborn babies.
A correlation was also found between thiopurine use and EBV-induced hemophagocytic lymphohistiocytosis (HLH), an aggressive disease associated with high mortality rates.3 With a third of patients estimated to be stopping thiopurine use due to adverse side effects, these new findings underline the need to find novel therapeutic approaches to tackle IBD.2
Lead researcher Professor Laurent Beaugerie, from the Department of Gastroenterology at Saint-Antoine Hospital, commented, “Clinicians need to be aware of the substantially increased risk of SVI in patients with IBD, which had previously remained unclear. Young IBD patients are the most vulnerable to the development of SVIs, as they are less likely to have been exposed to viruses such as EBV or CMV before. They will therefore mount a less effective immune response. Their risk is further elevated by the inhibiting effect of the immunosuppressive drugs they are treated with.”
The number of individual IBD cases, which encompasses both Crohn’s disease and ulcerative colitis, has shown a marked increase since 1990, rising from 3.6 million cases globally to over 6.8 million in 2017.4 Commenting on the increasingly heavy burden of IBD, Professor Beaugerie added, “The relation between IBD drugs and SVIs is especially concerning, as presently, hospitalisation due to the serious complications that accompany the disease is the main cost associated with the management of IBD. The growing prevalence of IBD across the globe will only add further to the pressure placed on healthcare structures.”
New treatment pathways such as nutritional therapies in Crohn’s disease and faecal microbiota transplantations (FMT), which are not evidenced to be associated with an increased risk of SVI, could potentially alleviate the strain placed on healthcare systems. Therapies such as these could transform the course of treatment and confer significant benefits to patients.
The study, which has cast new light on the strong association between IBD drugs and SVI, emphasises the need for further research and funding into the area to improve patient outcomes. An investigation into promising new treatments should become the next course of action if the risk of SVI in IBD patients is to be brought closer that of the general population.
References
The trial, led by the Murdoch Children’s Research Institute (MCRI) and published in Allergy: European Journal of Allergy and Clinical Immunology, saw specially trained paediatricians working in community clinics, where they could provide front-line allergy treatment and management advice. Children with three or fewer suspected food allergies took part in the trial while those with suspected anaphylaxis (a more severe type of food allergy) or more than three food allergies were excluded.
The trial resulted in faster assessment times, was more acceptable to families, and delivered similar quality of allergy care to specialist hospital-based clinics.
Based on these results, the trial team is calling for investment in a larger program to train community paediatricians, especially in regions where there are no child allergy specialists.
Lead author, MCRI’s Professor Harriet Hiscock, said 63% of those seen by a paediatrician in the community were treated without needing an allergist referral, freeing up valuable hospital resources.
“As rates of food allergy rise, specialist allergy services are valiantly struggling to manage demand, but waiting times to access these services are long,” Professor Hiscock said.
“In many regions around Australia, allergy care is primarily delivered by allergists, due to limited allergy training opportunities for general pediatricians and primary care physicians.”
Professor Hiscock said the study, which involved children aged 0-12 years, was the first to evaluate this community-based approach. A key component of the program is providing specialised allergy training to general paediatricians.
The study found out of the 115 participants in the community group, 81% saw a paediatrician by 12 months. This compared to 28% of 181 patients who received care at the RCH Allergy Clinic. Of these, 60% had not received an appointment at 12 months.
Time to assessment was also shorter, 2.4 months for a community paediatrician compared to 12 months for a hospital allergist.
Professor Hiscock said children in the community group reported fewer reactions to food and families were more satisfied with the overall process.
The site will be evaluating Rexgenero’s REX-001 in two Phase III trials, codenamed the SALAMANDER trials. The trials are being led by Mr Ian Williams, a Consultant Vascular Surgeon and the Principal Investigator at the site.
The University Hospital of Wales is participating in the trials through a consortium, the Midlands-Wales Advanced Therapy Treatment Centre (MW-ATTC), part of the Advanced Therapy Treatment Centre Network (ATTC) which aims to bring pioneering advanced therapy medicinal products (ATMPs) to patients. THE MW-ATTC has been working in collaboration with the Cardiff & Vale University Health Board to progress the initiation of the two SALAMANDER trials and is planning to activate new clinical trial sites in the Midlands in England shortly.
REX-001 represents a new class of regenerative medicines. It is an autologous cell therapy manufactured using the patient’s own bone marrow and consists of immune cells (lymphocytes, monocytes and granulocytes) and progenitor cells involved in immune modulation and tissue regeneration. It is administered as a single dose within 4 days after collection of bone marrow cells.
Ian Williams, Consultant Vascular Surgeon and Principal Investigator commented, “Chronic limb-threatening ischaemia is a serious disease with severe consequences and limited treatment options. There is a high unmet need for novel and innovative therapies – such as REX-001 – that have the potential to be a highly effective treatment and to reduce amputation and mortality rates amongst the patient population.”
Rexgenero, the company pioneering the development of REX-001, says that the experimental product has already demonstrated efficacy in Phase I/II studies. In the Phase II clinical trial, 82% of patients with non-healing ischaemic ulcers were healed within the first 12 months after a single administration dose of REX-001.
Joe Dupere, CEO of Rexgenero added, “Treating our first patient with REX-001 in the UK represents an important milestone for our Phase III program in diabetic patients with chronic-limb threatening ischaemia, a severe condition with high unmet need. With clinical trial sites and manufacturing bases now open across multiple countries in Europe, we are one step closer to completion of the Phase III studies and potential regulatory and market approval for an innovative and much-needed product.”
The trial is planning to treat a total of 60 patients with CLI and rest pain and 78 patients with CLI and non-healing ischaemic ulcers in two independent Phase III SALAMANDER trials in approximately 25 hospitals across Europe. In addition to the trial sites in the UK, recruitment for both trials at sites in Spain, Austria, Portugal, Poland, Hungary, the Netherlands and the Czech Republic is underway.
It is the first criteria developed specifically for this recently recognised disease.
A draft of the criteria was presented during the 2018 ACR/ARP Annual Meeting in Chicago. Since that time, the criteria team performed a second validation study, which confirmed the high sensitivity and specificity that was found in the first validation study.
IgG4-Related Disease (IgG4-RD) is an immune-mediated disease that may affect different organ systems and often mimics other diseases like Sjögren’s syndrome, pancreatic cancer, granulomatosis with polyangiitis (GPA), giant cell arteritis (GCA) and systemic lupus erythematosus (SLE or lupus). Only recognized in the last 10 to 15 years, IgG4-RD can cause fibro-inflammatory lesions in nearly any organ or multiple organs. Estimates suggest that IgG4-RD affects 180,000 people in the United States and many more worldwide.
“IgG4-RD is now recognised to be a worldwide condition that is seen not only by rheumatologists but also generalists and sub-specialists of nearly every kind,” said John H Stone, MD, MPH, professor of medicine at Harvard Medical School and director of the international panel of experts who developed the new criteria. “Clinical trials are now being developed in IgG4-RD and investigators need criteria on which to base patients’ inclusion or exclusion for such trials and other types of investigation.”
Classification criteria allow researchers to accurately identify patients for inclusion in clinical, epidemiologic and basic investigations. The panel of experts who developed the new classification criteria included investigators from rheumatology and other specialties from five continents, reflecting the worldwide impact of this disease.
In the criteria, classifying patients with IgG4-RD is a three-step process that carefully assesses data from four domains, which must make sense in the context of IgG4-RD. The process includes synthesising information from the patient’s clinical presentation, blood test results or serology, radiological findings and the pathology data. Few other diseases require such careful synthesis of various information to get an accurate diagnosis, and at this time, there is no single diagnostic test for the disease.
The 2019 ACR/EULAR Classification Criteria for IgG4-Related Disease were validated in a large cohort of patients and demonstrated excellent test performances. Dr. Stone feels they should be a highly useful contribution to future investigations in this disease, and will ultimately help improve the lives of patients with IgG4-RD.
“IgG4-RD is a disease that tends to afflict middle-aged to elderly individuals and often affects and damages the pancreas severely, making glucocorticoids a suboptimal therapy for this condition,” Dr. Stone says. “Clinical trials will help develop targeted therapies that spare toxicities from conventional treatments. Investigators need to have criteria like this to determine whether a patient should be classified as having IgG4-RD.”
2nd December 2019
The researchers say that their review of existing literature, published in Molecular Psychiatry, highlights how little research has been done into one of the world’s major killers, particularly among the most vulnerable groups.
The facts in relation to suicide are stark: 800,000 people die globally by suicide every year, the equivalent of one every 40 seconds. Suicide is the second leading cause of death globally among 15–29 year olds. More adolescents die by suicide than from cancer, heart disease, AIDS, birth defects, stroke, pneumonia, influenza, and chronic lung disease combined. As many as one in three adolescents think about ending their lives and one in three of these will attempt suicide.
“Imagine having a disease that we knew killed almost a million people a year, a quarter of them before the age of thirty, and yet we knew nothing about why some individuals are more vulnerable to this disease,” said Dr Anne-Laura van Harmelen, co-first author from the University of Cambridge. “This is where we are with suicide. We know very little about what’s happening in the brain, why there are sex differences, and what makes young people especially vulnerable to suicide.”
A team of researchers, including Hilary Blumberg, MD, John and Hope Furth Professor of Psychiatric Neuroscience at Yale, carried out a review of two decades’ worth of scientific literature relating to brain imaging studies of suicidal thoughts and behaviour. In total, they looked at 131 studies, which covered more than 12,000 individuals, looking at alterations in brain structure and function that might increase an individual’s suicide risk.
They identified two brain networks – and the connections between them – that appear to play an important role.
The first of these networks involves areas towards the front of the brain known as the medial and lateral ventral prefrontal cortex and their connections to other brain regions involved in emotion. Alterations in this network may lead to excessive negative thoughts and difficulties regulating emotions, stimulating thoughts of suicide.
The second network involves regions known as the dorsal prefrontal cortex and inferior frontal gyrus system. Alterations in this network may influence suicide attempt, in part, due to its role in decision making, generating alternative solutions to problems, and controlling behaviour.
The researchers suggest that if both networks are altered in terms of their structure, function or biochemistry, this might lead to situations where an individual thinks negatively about the future and is unable to control their thoughts, which might lead to situations where an individual is at higher risk for suicide.
“The review provides evidence to support a very hopeful future in which we will find new and improved ways to reduce risk of suicide,” said Professor Hilary Blumberg. “The brain circuitry differences found to converge across the many studies provide important targets for the generation of more effective suicide prevention strategies. “It is especially hopeful that scientists, such as my co-authors on this paper, are coming together in larger collaborative efforts that hold terrific promise.”
The majority of studies so far have been cross-sectional, meaning that they take a ‘snapshot’ of the brain, rather than looking over a period of time, and so can only relate to suicidal thoughts or behaviours in the past. The researchers say there is an urgent need for more research that looks at whether their proposed model relates to future suicide attempts and at whether any therapies are able to change the structure or function of these brain networks and thereby perhaps reduce suicide risk.
The review highlighted the paucity of research into suicide, particularly into sex differences and among vulnerable groups. Despite suicidal thoughts often first occurring as early as during adolescence, the majority of studies focused on adults.
“The biggest predictor of death by suicide is previous suicide attempt, so it’s essential that we can intervene as early as possible to reduce an individual’s risk,” said co-first author Dr Lianne Schmaal from the University of Melbourne. “For many individuals, this will be during adolescence. If we can work out a way to identify those young people at greatest risk, then we will have a chance to step in and help them at this important stage in their lives.”
Even more striking, despite the fact that transgender individuals are at increased risk for suicide, just one individual in the 131 samples included for the review was identified to be transgender.
In 2018, the researchers launched the HOPES (Help Overcome and Prevent the Emergence of Suicide) study, supported by the mental health research charity MQ. HOPES brings together data from around 4000 young people across 15 different countries in order to develop a model to predict who is at risk of suicide. Over the course of the project, the team will analyse brain scans, information on young people’s environment, psychological states and traits in relation to suicidal behaviour from young people from across the world, to identify specific, universal risk-factors.
29th November 2019
This technology could revolutionise the serodiagnosis of microbial, autoimmune and allergic disorders.
Now this team of researchers have applied the new concept for diagnostics of coeliac disease.
Screening of coeliac disease is recommended for patients with, for example, gastrointestinal coeliac patients. The screening test involves measurement of disease-specific antibodies from a blood sample.
The researchers gathered samples from 70 coeliacs at the Kuopio University Hospital, half from children and half from adults. Control samples from healthy donors were also collected. The samples were measured using the new assay and results compared with two currently used methods.
“The performance of the test was comparable to that of current methods. The prevailing method involves transporting the sample to a central laboratory and a multi-step procedure taking hours. With the new method, results can be achieved in less than half an hour by simply combining the sample and a reagent mix, waiting for a while and reading the result.”, Juuso Rusanen, MD, explains. He continues:
“We hope our rapid method could lower the threshold for screening of coeliac disease and thus help overcome the vast underdiagnosis of this relatively common condition.”
“Additionally, this is the first time the new method has been used for diagnostics of autoimmune disease. This is a promising result, and prompts the development of similar tests for diagnostics of other autoimmune disorders“, Rusanen points out.
Achieving seizure control within the first one to two hours is an independent predictor of patient outcomes, including significant disability and mortality.1
Using benzodiazepines as a first course of action is well established, and if given promptly and in sufficient doses will abort seizures in up to 70% of patients. However, best practice beyond this has been far less clear for treating this life-threatening condition.
That is, until the results of the Established Status epilepticus Treatment Trial (ESETT) trial were published this week in the New England Journal of Medicine – providing much needed results on what to do when first-line therapy fails.2
If benzodiazepines fail to work, the decision to administer a second drug needs to be taken within 5-10 minutes, with phenytoin being the traditional choice and the only drug licensed for use in SE. Newer alternatives, specifically valproate and levetiracetam have gained popularity, but until now not been rigorously evaluated in a clinical trial setting, leaving clinicians uncertain as to which drug to use and at what doses.
Our double blind randomised controlled trial in 384 patients showed that all three drugs are effective in stopping seizures in around half of patients that have not responded to benzodiazepines, sparing many patients from endotracheal intubation and intensive care unit stays. Each drug was found to be equally effective in stopping seizures, with no significant differences in terms of drug safety when comparing across outcomes including life-threatening hypotension, heart problems, seizure recurrence and death.
Cumulative trials in SE over the years now support an evidenced based sequence of treatment, to which the vast majority of patients will SE will respond. These started 20 years ago with the Veterans Affairs co-operative3 and Pre-Hospital Treatment of SE studies,4 through to the 2012 RAMPART study.5 This list now includes ESETT and two open paediatric studies also published this year, ConSEPT6 and EclipSE.7
Looking at the broader picture, I believe valproate and levetiracetam have other practical advantages making them preferable to phenytoin.
Phenytoin takes at least double the time (20 minutes or more) to administer, and can exacerbate seizures in some types of epilepsy, with multiple potential drug interactions in an already critically ill population often needing multiple medications. Life threatening hypotension and cardiac arrhythmias, which are already risks in SE, are also recognised side effects not seen with the other agents.
When it comes to maintenance therapy, phenytoin is rarely used as it has been superseded by newer agents with better tolerability profiles, including valproate and levetiracetam. Finally, of reports over 5 years to the UK National Patient Safety Agency,8 phenytoin was the only drug where loading dose errors were associated with fatalities.
The results from ESSET should give clinicians the confidence to use valproate or levetiracetam to treat SE using the high loading doses utilised in the study.
Our focus now must include ways to better prevent or treat the remaining refractory SE patients, and putting the evidence we do have into practice. A sub-study within ESETT also demonstrated frequent under-dosing with benzodiazepines,9 and in my own centre and elsewhere I know the same is often true of second line agents.
We need to trust the evidence we have, be braver with dosing and act quickly with the effective medications we have. If we follow guidance and take prompt action, we will all be better set to provide the best care and save lives.
References
About the author
Hannah Cock is Professor of Epilepsy and Medical Education at St George’s, University of London, and a consultant neurologist in the Atkinson Morley Regional Epilepsy Network at St George’s University Hospitals NHS Foundation Trust. She has been involved in status epilepticus research for over 20 years, is now course director for medicine at St George’s, University of London, and the local Status Epilepticus lead.
Declaration
Prof Cock was a principal investigator on the ESETT study, funded by Grants U01NS073476, U01NS088034, U01NS088023, U01NS056975, U01NS059041, and R01NS099653 from the National Institute of Neurological Disorders and Stroke, USA. She also reports: personal fees from Sage Pharmaceuticals Ltd, from Eisai Europe Ltd, UCB Pharma Ltd, UK Epilepsy Nurse Specialist Association, Bial and Eisai outside the submitted work. Also non-financial support from Special Products Ltd, the International League Against Epilepsy Epilepsy Certification (education) Task Force, and the European Academy of Neurology.
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