The clinical manifestations of the polyomaviruses BK and JC in immunocompromised patients include BK virus (BKV) induced haemorrhagic cystitis and nephropathy, and JC virus (JCV) associated ...progressive multifocal leukoencephalopathy (PML) and are typically a consequence of impaired adaptive immunity in the host. To date, little clinical success has been achieved with antiviral agents or other drug therapies to treat these conditions. Here we review the methods and outcomes of the most recent clinical studies utilising adoptive immunotherapy with BK and/or JC virus-specific T-cells (VST) as either prophylaxis or treatment alternatives.
In the last 12-18 months, several clinical trials have been published in the post-haemopoietic stem cell transplant (HSCT) setting showing good clinical success with the use of VST for treatment of BK viremia ± haemorrhagic cystitis. Between 82 and 100% clinical response has been observed in haemorrhagic cystitis using either third-party or donor-derived VST. The therapy was well tolerated with few cases of graft versus host disease in HSCT recipients, but immune mediated renal allograft loss was observed in one renal transplant recipient. Studies using BKV/JCV VST to treat PML are hindered by few patients who are sufficiently stable to receive VST. In a condition that otherwise carries such poor prognosis, VST were associated with clearance of JC virus, clinical and radiological improvement in some patients. Immune reconstitution inflammatory syndrome was a noted adverse event.
Restoration of BK and JC virus immunity using VST immunotherapy has shown good clinical outcomes in BKV associated infections. Further evaluation with the administration of VST earlier in the course of disease is warranted for the treatment of BKV associated nephropathy in renal allograft and in JCV PML. In both indications, larger cohorts and standardisation of dosing and outcome measures would be of benefit.
Cardiovascular disease is a leading cause of morbidity and mortality in individuals with type 2 diabetes mellitus. These high-risk patients benefit from aggressive risk factor management, with blood ...pressure and low-density lipoprotein-cholesterol treatment, glycemic control, kidney protection, and lifestyle intervention. There are several recommendation and guideline documents across cardiology, endocrinology, nephrology, and general medicine professional societies from the United States and Europe with recommendations for cardiovascular risk reduction in patients with type 2 diabetes mellitus. Although there are some noteworthy differences, particularly in risk stratification, low-density lipoprotein-cholesterol and blood pressure treatment targets, and the use of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, overall there is considerable alignment across recommendations from different professional societies.
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•Vascular calcification is a highly regulated, cell-mediated process that is strongly associated with CKD and confers increased risk for incident CV events.•Multiple pathways link ...vascular calcification with CKD; however, they remain incompletely understood, and the development of targeted therapies has been underwhelming.•Illumination of the causal steps and natural history that link vascular calcification to CV events will affirm its role as a CV risk factor and accelerate drug discovery and therapeutic translation.
Cardiovascular (CV) disease remains an important cause of morbidity and mortality for patients with chronic kidney disease (CKD). Although clustering of traditional risk factors with CKD is well recognized, kidney-specific mechanisms are believed to drive the disproportionate burden of CV disease. One perturbation that is frequently observed at high rates in patients with CKD is vascular calcification, which may be a central mediator for an array of CV sequelae. This review summarizes the pathophysiological bases of intimal and medial vascular calcification in CKD, current strategies for diagnosis and management, and posits vascular calcification as a risk marker and therapeutic target.
Prostate cancer is the commonest, non-cutaneous cancer in men. At present, there is no cure for the advanced, castration-resistant form of the disease. Estrogen has been shown to be important in ...prostate carcinogenesis, with evidence resulting from epidemiological, cancer cell line, human tissue and animal studies. The prostate expresses both estrogen receptor alpha (ERA) and estrogen receptor beta (ERB). Most evidence suggests that ERA mediates the harmful effects of estrogen in the prostate, whereas ERB is tumour suppressive, but trials of ERB-selective agents have not translated into improved clinical outcomes. The role of ERB in the prostate remains unclear and there is increasing evidence that isoforms of ERB may be oncogenic. Detailed study of ERB and ERB isoforms in the prostate is required to establish their cell-specific roles, in order to determine if therapies can be directed towards ERB-dependent pathways. In this review, we summarise evidence on the role of ERB in prostate cancer and highlight areas for future research.
Purpose of Review
For more than 20 years there has been considerable interest in the development of pharmacological inhibitors of cholesteryl ester transfer protein (CETP) by virtue of their ability ...to raise levels of high-density lipoprotein cholesterol. This review endeavors to integrate existing data from prior clinical trials with emerging data to understand whether there is a pathway forward to develop CETP inhibitors to prevent cardiovascular disease.
Recent Findings
Large clinical trials have proved disappointing with successive reports of a failure to reduce cardiovascular events. The one clinical development program that did demonstrate a reduction in cardiovascular risk found adipose tissue accumulation and did not proceed for regulatory approval. More recent observations suggest that less CETP activity may prevent cardiovascular events, but due to lipid lowering rather than raising high-density lipoprotein cholesterol. In addition, treatment with CETP inhibitors appears to have a beneficial impact on glycemic control in the setting of diabetes.
Summary
Advances in the field of CETP inhibition suggest a potentially protective effect on the risk of both cardiovascular disease and diabetes. This has implications for how to best design future clinical development programs and leaves the door open to potentially bring CETP inhibitors to the preventive cardiology clinic.
Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown.
To examine the effect of progressive weight gain on the substrate for AF.
Thirty sheep ...were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor β1, and connective tissue growth factor.
Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P<.001), increase in conduction heterogeneity index (P<.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor β1 (P = .02) and platelet-derived growth factor (P = .02) levels.
Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF.
The structures and biological activities of natural products have often provided inspiration in drug discovery. The functional benefits of natural products to the host organism steers the evolution ...of their biosynthetic pathways. Here, we describe a discovery approach--which we term activity-directed synthesis--in which reactions with alternative outcomes are steered towards functional products. Arrays of catalysed reactions of α-diazo amides, whose outcome was critically dependent on the specific conditions used, were performed. The products were assayed at increasingly low concentration, with the results informing the design of a subsequent reaction array. Finally, promising reactions were scaled up and, after purification, submicromolar ligands based on two scaffolds with no previous annotated activity against the androgen receptor were discovered. The approach enables the discovery, in tandem, of both bioactive small molecules and associated synthetic routes, analogous to the evolution of biosynthetic pathways to yield natural products.
To explore the effect of SMS nudge messages amongst people with varying health literacy on their intention to get a Heart Health Check.
A 3 (Initial SMS: scarcity, regret, or control nudge) x 2 ...(Reminder SMS: social norm or control nudge) factorial design was used in a hypothetical online experiment. 705 participants eligible for Heart Health Checks were recruited. Outcomes included intention to attend a Heart Health Check and psychological responses.
In the control condition, people with lower health literacy had lower behavioural intentions compared to those with higher health literacy (p = .011). Scarcity and regret nudges closed this gap, resulting in similar intention levels for lower and higher health literacy. There was no interactive effect of the reminder nudge and health literacy (p = .724).
Scarcity and regret nudge messages closed the health literacy gap in behavioural intentions compared to a control message, while a reminder nudge had limited additional benefit. Health literacy should be considered in behavioural intervention evaluations to ensure health equity is addressed.
Results informed a national screening program using a universal precautions approach, where messages with higher engagement for lower health literacy groups were used in clinical practice.
•People with lower health literacy are less likely to access health screening.•Nudges could be a cost-effective way to encourage the uptake of Heart Health Checks.•Type of nudge may interact with health literacy to change intention and behaviour.•Health interventions should consider health literacy to reduce health disparities.
Cardiovascular disease (CVD) is the most common cause of morbidity and mortality for patients with diabetes mellitus (DM). Although the burden of atherosclerotic CVD (ASCVD) is well documented, heart ...failure (HF) has been an under-appreciated CVD complication of DM. However, as more patients with DM live longer and survive acute ASCVD events, the distribution of CVD complications has evolved. This review summarizes the epidemiology of DM, the relative risk and prognosis of both ASCVD and HF following a diagnosis of DM, and the likelihood of cause-specific CVD mortality in patients with DM.
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