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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.
6th December 2019
However, inflammation and states of hypervolaemia may negatively affect its intravascular persistence due to endothelial glycocalyx shedding.
In this study, the authors sought to determine the pharmacological and volumetric profile of 20% albumin, infused at a constant rate for 30 minutes, in patients undergoing major abdominal surgery.
The infusion diluted plasma volume by almost twice the infused fluid volume in both patients and healthy volunteers, and no differences were seen in plasma volume expansion over time. The increase in plasma albumin observed after 30 minutes post-infusion was significantly greater for the group undergoing surgery than for the control group.
Longer intravascular persistence times were seen for overweight patients, but age and sex did not influence outcomes. Mean arterial pressure values were lower for postoperative patients versus volunteers before and after the infusion, and plasma C-reactive protein levels were higher, but the levels of glycocalyx shedding products in the plasma and urine did not differ significantly between groups.
These observations show that 20% albumin is a safe option in the postoperative period.
5th December 2019
Some studies suggest that albumin may have additional anti-inflammatory and antioxidant benefits during cardiac surgery. However, potential adverse effects include acute kidney injury in patients with underlying kidney dysfunction.
There is currently evidence showing the superiority of albumin versus crystalloids in preserving platelet counts during on-pump surgery, but it is not clear if its use leads to improved clinical outcomes in this specific setting.
In this retrospective observational study, 6188 patients undergoing on-pump cardiac surgery for isolated valve, isolated coronary artery bypass grafting, or two or more procedures requiring cardiopulmonary bypass, were evaluated for survival and renal outcomes according to the type of fluid therapy administered.
Propensity score matching was used for controlling for confounding factors. Compared with patients who received crystalloid solutions alone, patients who received 5% albumin concomitantly showed decreased risk of in-hospital mortality (2.3% versus 3.3%) and a lower all-cause 30-day hospital readmission rate (10% versus 14%). No differences were seen in overall major morbidity or severity of acute kidney injury.
These data support the use of albumin in cardiac surgery when colloids are indicated, but a causal effect between the use of this colloid and survival benefits cannot be established.
The type and amount of fluid administered is known to influence renal outcomes. Whereas isotonic crystalloid solutions are largely preferred over colloid substances for critically ill patients, albumin solutions may be indicated in specific cases where there is high fluid demand.
By contrast, artificial colloid formulations have been associated with kidney-related mortality.
Capacity of urine output and serum creatinine levels are commonly used to measure renal function, but they vary according to type of fluid and need to be used with caution when assessing the effectiveness of fluid therapy for an individual patient.
This article discusses the usefulness of these measures of renal dysfunction as well as the requirement of fluid therapy in renal resuscitation and reviews the currently available data from studies examining the relationship of fluid therapy and acute kidney injury and mortality.
The authors also cover the underlying mechanisms of kidney injury for each type of fluid, emphasising that the administration of fluids should not constitute an automatic response to oliguria and increased creatinine levels in critically ill patients.
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.
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.”