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Research conducted by Professor Tim Goodship and co-workers at Newcastle has had a profound effect on the prognosis for patients with atypical haemolytic uraemic syndrome (aHUS). By engaging in research on the genetic factors underlying the disease they developed an understanding of the molecular mechanisms responsible. Identifying that the majority of patients with aHUS have either acquired or inherited abnormalities of the regulation of complement (part of the immune system) led to the establishment of a UK national service for genetic screening and treatment with the complement inhibitor eculizumab. As eculizumab is now available to patients in England, the progression to end-stage renal failure can be prevented and patients already on dialysis will soon be successfully transplanted.
Congenital myasthenic syndromes (CMS) are inherited neuromuscular disorders caused by defects at neuromuscular junctions, which are often a result of acetylcholine receptor gene mutations. A subset of CMS patients (around 14% in the US and Europe) have limb-girdle myasthenia (LGM). This disease can be highly disabling with symptoms including increasing weakness of skeletal muscles. As a result of collaborative work between Newcastle and Oxford, it was determined that many LGM patients have a mutation of the Dok-7 gene (unrelated to the acetylholine receptor), and do not, therefore, respond to standard CMS treatments. Since then, a number of additional mutations have been discovered, and genetic testing is now available for the majority of known LGM-causative genes. Crucially, Dok-7 patients, and those with other non-receptor related mutations, can now be diagnosed accurately and treated effectively, with ephedrine and salbutamol (in the US, albuterol). This significantly improves these patients' quality of life by enabling them to walk and breathe unassisted.
Colorectal cancer is a common disease, which frequently causes death or morbidity, either because of failure to control the primary tumour or failure to prevent distant metastases. Leeds researchers have devised new treatment approaches using chemotherapy and radiotherapy and tested them in large randomised controlled trials which have led to major changes in clinical practice in the management of rectal cancer and advanced colorectal cancer (aCRC), driving clinical decision-making and improving outcomes for patients. This includes better-evidenced treatment for elderly patients and patient stratification on the basis of molecular biomarkers.
Warfarin is an anti-coagulant drug prescribed to tens of millions of people in the UK and US who are at high risk of developing blood clots. Because individual sensitivity to warfarin varies in the population there is a risk of overdosing the drug and causing serious bleeding and even stroke in many people when starting treatment. In 1999 researchers at Newcastle University were the first to demonstrate a statistically significant link between a person's genotype and the appropriate dose of warfarin. In 2010 the US Food and Drug Administration (FDA) mandated inclusion of a table of dose recommendations based on genotype in the warfarin prescribing information leaflet accompanying the drug. Newcastle research forms the basis of the 2009 international standard algorithm for gene-guided dosing of warfarin. This approach has been adopted by large US medical centres and the FDA states that it will prevent 17,000 strokes a year in the US.
Malignant pleural mesothelioma (MPM) is a treatable but incurable cancer that originates in the cells lining the lungs. Over 14,000 people worldwide are diagnosed annually with MPM. Antifolates are often used in cancer therapy, but side effects are a major issue. A retrospective analysis of cancer trials and phase 1 trial of MPM patients, carried out by Newcastle in collaboration with Eli Lilly Pharmaceuticals, determined that plasma homocysteine levels were a good predictor of drug toxicity in cancer patients treated with the antifolate pemetrexed, and that this drug was well tolerated by patients with low homocysteine levels. It was also determined that pemetrexed treatment should be supplemented with vitamin B12 as well as folic acid, to reduce drug toxicity. Ultimately, this permitted the continued development of pemetrexed, which otherwise would have been too toxic for clinical use. It is now the only licensed drug for MPM treatment in combination with platinum-based chemotherapy.
Researchers at the University of Bristol have developed tests to track low-level leukaemia — `minimal residual disease' (MRD) — in children with acute lymphoblastic leukaemia (ALL) down to levels thousands of times lower than detectable by light microscopy. These tests have become the gold standard for monitoring of leukaemic response in clinical trials. MRD testing has been shown in 2013 to allow safe de-intensification of treatment for one-fifth of patients treated nationally, with substantial savings in toxicity and treatment-related expense. The same techniques have also improved worldwide understanding of how disease clearance is related to success after haemopoietic stem cell transplantation.
Research at the University of Nottingham has defined the clinical phenotype and management of lymphangioleiomyomatosis, a rare and often fatal multisystem disease affecting 1 in 200,000 women worldwide. The group has led the development and evaluation of new therapies and diagnostic strategies which are now part of routine clinical care. The research has underpinned the transformation of this previously under recognised and untreatable disease into a condition recognised by respiratory physicians, with international clinical guidelines, patient registries, clinical trials, specific treatments and a UK specialist clinical service.
Long-standing research led by Prof. O'Rahilly (Department of Clinical Biochemistry) into the genetic and biochemical basis of severe insulin resistance syndromes, has led to improvements in diagnosis and care of patients internationally. These advances have facilitated revision of existing clinical classifications and implementation of novel diagnostic and management algorithms for these conditions. The clinical applicability of this research was recognised in 2011 by the Department of Health-England who have commissioned a national severe insulin resistance service in Cambridge, with support totalling ~£450,000 per annum.
Researchers at the University of Manchester (UoM) have made a significant impact nationally and internationally on improving the outcome for children with acute lymphoblastic leukaemia (ALL) (~450 pa in the UK). The changes in clinical practice based on our research are now national standards of care for children with de novo and relapsed ALL in the UK and Ireland. Other international groups have adopted key findings from the results of our frontline trials. Our relapse protocol for childhood ALL underpins European and North American strategy for the management of relapsed disease.
University of Glasgow research has led to the adoption of first-line chemotherapy for ovarian cancer, which has improved patient survival by 11% and has been used to treat 66% of women with ovarian cancer since January 2011 in the West of Scotland Cancer Care Network alone. These therapies are recommended by guidelines for ovarian cancer treatment in the USA, Europe and the UK. The USA guidelines are disseminated to 4.3 million people worldwide and the European guidelines reach 15,000 health professionals. The UK guidelines are used to identify those drugs that are funded by the NHS and used in NHS hospitals.