Comparative assessment of 18F‐Mefway as a serotonin 5‐HT1A receptor PET imaging agent across species: Rodents,nonhuman primates,and humans

We have developed ¹⁸F‐trans‐Mefway (¹⁸F‐Mefway) for positron emission tomography (PET) imaging studies of serotonin 5‐HT_1A receptors which are implicated in various brain functions. Translation of imaging the 5‐HT_1A receptor in animal models to humans will facilitate an understanding of the role of the receptor in human brain disorders. We report comparative brain distribution of ¹⁸F‐Mefway in normal mice, rats, monkeys, and healthy human volunteers. Mefway was found to be very selective, with subnanomolar affinity for the 5‐HT_1A receptor. Affinities of >55 nM were found for all other human‐cloned receptor subtypes tested. Mefway was found to be a poor substrate (>30 μM) for the multidrug resistance 1 protein, suggesting low likelihood of brain uptake being affected by P‐glycoprotein. Cerebellum was used as a reference region in all imaging studies across all species due to the low levels of ¹⁸F‐Mefway binding. Consistent binding of ¹⁸F‐Mefway in cortical regions, hippocampus, and raphe was observed across all species. ¹⁸F‐Mefway in the human brain regions correlated with the known postmortem distribution of 5‐HT_1A receptors. Quantitation of raphe was affected by the resolution of the PET scanners in rodents, whereas monkeys and humans showed a raphe to cerebellum ratio of approximately 3. ¹⁸F‐Mefway appears to be an effective 5‐HT_1A receptor imaging agent in all models, including humans. ¹⁸F‐Mefway therefore may be used to quantify 5‐HT_1A receptor distribution in brain regions for the study of various CNS disorders. J. Comp. Neurol. 524:1457–1471, 2016. © 2015 Wiley Periodicals, Inc.     

Phase II anti-inflammatory and immune-modulating drugs for acute ischaemic stroke

Introduction: Stroke is the second leading cause of death worldwide and the leading cause of adult neurological disability. Despite advances in stroke unit care, and increasing use of thrombolysis, there remains an urgent need for safe and effective treatments for acute ischaemic stroke. However, this is against a backdrop of multiple failures in translational drug development. Cerebral ischaemia initiates a complex cascade of immune and inflammatory pathways in the brain microvasculature and periphery, which contribute to the evolution of cerebral injury, resolution and repair. Targeting specific inflammatory or immune pathways, therefore, represents an attractive treatment strategy in acute ischaemic stroke. Although anti-inflammatory drugs have already failed in clinical trial development, several are currently at the Phase II developmental stage.

Areas covered: The authors highlight several candidate drugs, which modulate a range of inflammatory and immune pathways, and have been investigated in pre-clinical and Phase II studies to date.

Expert opinion: Drugs targeting inflammatory and immune pathways offer theoretical advantages including potentially longer therapeutic time windows and effects complementary to thrombolysis (ameliorating reperfusion injury). Fundamental changes in the approach to pre-clinical and clinical drug development are required to facilitate successful translation of promising candidate drugs into clinical practice.     

4th international conference on tumor progression and therapeutic resistance: meeting report

The fourth international conference on tumor progression and therapeutic resistance organized in association with GTCbio was held in Boston, MA from March 9 to 11, 2014. The meeting attracted a diverse group of experts in the field of cancer biology, therapeutics and medical oncology from academia and industry. The meeting addressed the current challenges in the treatment of cancer including tumor heterogeneity, therapy resistance and metastasis along with the need for improved biomarkers of tumor progression and clinical trial design. Keynote speakers included Clifton Leaf, Editor at Fortune Magazine, Dr. Mina Bissell from the Lawrence Berkeley National Laboratory and Dr. Levi Garraway from the Dana Farber Cancer Institute. The meeting featured cutting edge tools, preclinical models and the latest basic, translational and clinical research findings in the field.     

Cardiorenal protection with SGLT2: Lessons from the cardiovascular outcome trials

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of drugs that were primarily developed for the treatment of type 2 diabetes mellitus. However, these agents have shown to provide additional beneficial effects. We will discuss three main topics regarding the use of SGLT2 inhibitors: noncardiovascular effects, cardiovascular benefits, and novel clinical indications. Multiple clinical trials and preliminary studies across varying disciplines have shown that these agents exhibit cardiorenal‐protective benefits, retinoprotective benefits, and may aid in weight loss without causing marked hypoglycemia. Therefore, these agents represent an avenue in clinical practice to manage comorbid conditions in the hyperglycemic patient. Because of their multifaceted effects and robust action, SGLT2 inhibitors represent therapy options for providers that not only provide beneficial clinical results but also reduce total patient drug burden.     

Thomas Willis,a pioneer in translational research in anatomy (on the 350th anniversary of Cerebri anatome)

The year 2014 marked the 350th anniversary of the publication in London of Cerebri anatome, a ground‐breaking work of neuroscience heavily influenced by the political and cultural context of Baroque Europe and mid‐17th century England. This article aims to review the work of the English physician and anatomist Thomas Willis, specifically with regard to the contents of his Cerebri anatome. Willis's academic and professional career was influenced by the turbulent period of the English Civil War during which he studied medicine. Willis went from chemistry to dissection arguably because of his need to justify the body‐brain‐soul relationship. As a result, he became a fellow of a select club of eminent experimentalists, and afterward was a Fellow of the Royal Society. Later on, he went to London, leaving the academic life to dedicate himself fully to the profession of medicine. As a physician, Willis did not base his practice on aphorisms but on a ‘bench to bedside’ approach to medicine, while studying neuroanatomy – covering embryology, comparative anatomy and pathological anatomy – as a basis for the comprehension of neurological pathology. He developed innovative anatomical methods for the preservation and dissection of the brain, injection of coloured substances and illustration of his findings. In Cerebri anatome, Willis recognized the cerebral cortex as the substrate of cognition. He also claimed that the painful stimuli came from the meninges, but not from the brain itself. He explained for the first time the pathological and functional meaning of the brain's circular arterial anastomosis, which is named after him. He also specified some features of the cranial origin of the sympathetic nerves and coined the term ‘neurologie’. Cerebri anatome marked the transition between the mediaeval and modern notions of brain function, and thus it is considered a cornerstone of clinical and comparative anatomy of the nervous system. The new contributions and methods employed by Willis justify his place as a father of neurology and a pioneer of translational research.     

Genetic Variation in Caveolin‐1 Correlates With Long‐Term Pancreas Transplant Function

Pancreas transplantation is a successful treatment for a selected group of people with type 1 diabetes. Continued insulin production can decrease over time and identifying predictors of long‐term graft function is key to improving survival. The aim of this study was to screen subjects for variation in the Caveolin‐1 gene (Cav1), previously shown to correlate with long‐term kidney transplant function. We genotyped 435 pancreas transplant donors and 431 recipients who had undergone pancreas transplantation at the Oxford Transplant Centre, UK, for all known common variation in Cav1. Death‐censored cumulative events were analyzed using Kaplan–Meier and Cox regression. Unlike kidney transplantation, the rs4730751 variant in our pancreas donors or transplant recipients did not correlate with long‐term graft function (p = 0.331–0.905). Presence of rs3801995 TT genotype (p = 0.009) and rs9920 CC/CT genotype (p = 0.010) in our donors did however correlate with reduced long‐term graft survival. Multivariate Cox regression (adjusted for donor and recipient transplant factors) confirmed the association of rs3801995 (p = 0.009, HR = 1.83;[95% CI = 1.16–2.89]) and rs9920 (p = 0.037, HR = 1.63; [95% CI = 1.03–2.73]) with long‐term graft function. This is the first study to provide evidence that donor Cav1 genotype correlates with long‐term pancreas graft function. Screening Cav1 in other datasets is required to confirm these pilot results.     

Chimerism,Graft Survival,and Withdrawal of Immunosuppressive Drugs in HLA Matched and Mismatched Patients After Living Donor Kidney and Hematopoietic Cell Transplantation

Thirty‐eight HLA matched and mismatched patients given combined living donor kidney and enriched CD34⁺ hematopoietic cell transplants were enrolled in tolerance protocols using posttransplant conditioning with total lymphoid irradiation and anti‐thymocyte globulin. Persistent chimerism for at least 6 months was associated with successful complete withdrawal of immunosuppressive drugs in 16 of 22 matched patients without rejection episodes or kidney disease recurrence with up to 5 years follow up thereafter. One patient is in the midst of withdrawal and five are on maintenance drugs. Persistent mixed chimerism was achieved in some haplotype matched patients for at least 12 months by increasing the dose of T cells and CD34⁺ cells infused as compared to matched recipients in a dose escalation study. Success of drug withdrawal in chimeric mismatched patients remains to be determined. None of the 38 patients had kidney graft loss or graft versus host disease with up to 14 years of observation. In conclusion, complete immunosuppressive drug withdrawal could be achieved thus far with the tolerance induction regimen in HLA matched patients with uniform long‐term graft survival in all patients.     

Rotavirus in Organ Transplantation: Drug‐Virus‐Host Interactions

Although rotavirus is usually recognized as the most common etiology of diarrhea in young children, it can in fact cause severe diseases in organ transplantation recipients irrespective of pediatric or adult patients. This comprehensive literature analysis revealed 200 cases of rotavirus infection with 8 related deaths in the setting of organ transplantation been recorded. Based on published cohort studies, an average incidence of 3% (187 infections out of 6176 organ recipients) was estimated. Rotavirus infection often causes severe gastroenteritis complications and occasionally contributes to acute cellular rejection in these patients. Immunosuppressive agents, universally used after organ transplantation to prevent organ rejection, conceivably play an important role in such a severe pathogenesis. Interestingly, rotavirus can in turn affect the absorption and metabolism of particular immunosuppressive medications via several distinct mechanisms. Even though rotaviral enteritis is self‐limiting in general, infected transplantation patients are usually treated with intensive care, rehydration and replacement of nutrition, as well as applying preventive strategies. This article aims to properly assess the clinical impact of rotavirus infection in the setting of organ transplantation and to disseminate the interactions among the virus, host and immunosuppressive medications.     

HLA Epitopes as Viewed by Antibodies: What Is it All About?

The need for new approaches to define HLA antibodies, in the context of organ transplantation, is intensely debated among HLA professionals. In this review, we sought to provide background and perspective to current understanding of the immunogenicity of HLA mismatches with respect to the humoral alloimmune response and the definition of B cell epitopes. Initial data suggest that epitope matching not only assists in defining better matches for the current transplant, but also minimizes the risk of developing de novo HLA‐donor‐specific‐antibodies posttransplant. In other words, other than lowering the risk of current graft rejection, epitope matching is likely to lower overall future sensitization levels and thus increases the likelihood of finding a compatible donor when the need for a retransplantation arises. More detailed knowledge of epitopes makes it possible to investigate what constitutes permissible versus non‐permissible HLA mismatches. The currently available evidence suggest that epitope matching is the most rational way to decrease the risk of HLA‐linked transplant rejection. This review is aimed at stimulating further and more intense collaborative effort in this field.