Trends in Therapeutic Conjugates: Bench to Clinic.

In recent years, therapeutic conjugates have attracted considerable attention as a new class of drug due to their unique pharmacological properties, especially from the pharmaceutical community. Their molecular structure tunability, improved targeting specificity, and therapeutic efficacy have been demonstrated in a wide range of research and clinical applications. In this topical review, we summarize selected recent advances in bioconjugation strategies for the development of therapeutic conjugates, their emerging application in clinical settings, as well as perspectives on the direction of future research.

Small diameter helical vascular scaffolds support endothelial cell survival.

There is an acute clinical need for small-diameter vascular grafts as a treatment option for cardiovascular disease. Here, we used an intelligent design system to recreate the natural structure and hemodynamics of small arteries. Nano-fibrous tubular scaffolds were fabricated from blends of polyvinyl alcohol and gelatin with inner helices to allow a near physiological spiral flow profile, using the electrospinning technique. Human coronary artery endothelial cells (ECs) were seeded on the inner surface and their viability, distribution, gene expression of mechanosensitive and adhesion molecules compared to that in conventional scaffolds, under static and flow conditions. We show significant improvement in cell distribution in helical vs. conventional scaffolds (94% ±â€¯9% vs. 82% ±â€¯7.2%; P < 0.05) with improved responsiveness to shear stress and better ability to withhold physiological pressures. Our helical vascular scaffold provides an improved niche for EC growth and may be attractive as a potential small diameter vascular graft.

Engineered drug delivery devices to address Global Health challenges.

There is a dire need for innovative solutions to address global health needs. Polymeric systems have been shown to provide substantial benefit to all sectors of healthcare, especially for their ability to extend and control drug delivery. Herein, we review polymeric drug delivery devices for vaccines, tuberculosis, and contraception.

Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology.

The cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in patient outcomes and therapy options, we investigated the impact of variations on the intermolecular interactions across the thin filament complex as an example of an unbiased systems biology method to better define clinical prognosis to aid future management options. We present a novel unbiased dynamic model to define and analyse the functional, structural and physico-chemical consequences of genetic variations among the troponins. This was subsequently integrated with clinical data from accessible global multi-centre systematic reviews of familial cardiomyopathy cases from 106 articles of the literature: 136 disease-causing variations pertaining to 981 global clinical cases. Troponin T variations showed distinct pathogenic hotspots for dilated and hypertrophic cardiomyopathies; considering the causes of cardiovascular death separately, there was a worse survival in terms of sudden cardiac death for patients with a variation at regions 90-129 and 130-179 when compared to amino acids 1-89 and 200-288. Our data support variations among 90-130 as being a hotspot for sudden cardiac death and the region 131-179 for heart failure death/transplantation outcomes wherein the most common phenotype was dilated cardiomyopathy. Survival analysis into regions of high risk (regions 90-129 and 130-180) and low risk (regions 1-89 and 200-288) was significant for sudden cardiac death (p = 0.011) and for heart failure death/transplant (p = 0.028). Our integrative genomic, structural, model from genotype to clinical data integration has implications for enhancing clinical genomics methodologies to improve risk stratification.

Gastrointestinal synthetic epithelial linings.

Epithelial tissues line the organs of the body, providing an initial protective barrier as well as a surface for nutrient and drug absorption. Here, we identified enzymatic components present in the gastrointestinal epithelium that can serve as selective means for tissue-directed polymerization. We focused on the small intestine, given its role in drug and nutrient absorption and identified catalase as an essential enzyme with the potential to catalyze polymerization and growth of synthetic biomaterial layers. We demonstrated that the polymerization of dopamine by catalase yields strong tissue adhesion. We characterized the mechanism and specificity of the polymerization in segments of the gastrointestinal tracts of pigs and humans ex vivo. Moreover, we demonstrated proof of concept for application of these gastrointestinal synthetic epithelial linings for drug delivery, enzymatic immobilization for digestive supplementation, and nutritional modulation through transient barrier formation in pigs. This catalase-based approach to in situ biomaterial generation may have broad indications for gastrointestinal applications.

Gene selection for cancer classification with the help of bees.

BACKGROUND: Development of biologically relevant models from gene expression data notably, microarray data has become a topic of great interest in the field of bioinformatics and clinical genetics and oncology. Only a small number of gene expression data compared to the total number of genes explored possess a significant correlation with a certain phenotype. Gene selection enables researchers to obtain substantial insight into the genetic nature of the disease and the mechanisms responsible for it. Besides improvement of the performance of cancer classification, it can also cut down the time and cost of medical diagnoses. METHODS: This study presents a modified Artificial Bee Colony Algorithm (ABC) to select minimum number of genes that are deemed to be significant for cancer along with improvement of predictive accuracy. The search equation of ABC is believed to be good at exploration but poor at exploitation. To overcome this limitation we have modified the ABC algorithm by incorporating the concept of pheromones which is one of the major components of Ant Colony Optimization (ACO) algorithm and a new operation in which successive bees communicate to share their findings. RESULTS: The proposed algorithm is evaluated using a suite of ten publicly available datasets after the parameters are tuned scientifically with one of the datasets. Obtained results are compared to other works that used the same datasets. The performance of the proposed method is proved to be superior. CONCLUSION: The method presented in this paper can provide subset of genes leading to more accurate classification results while the number of selected genes is smaller. Additionally, the proposed modified Artificial Bee Colony Algorithm could conceivably be applied to problems in other areas as well.

Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.

BACKGROUND: Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects," associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of beta-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of alpha-tropomyosin (TPM1). Routine genetic screening of HCM patients for specific mutations is anticipated to provide important diagnostic and prognostic information. The frequency and associated phenotype of these mutations in a large, unselected cohort of HCM is unknown. METHODS AND RESULTS: A total of 293 unrelated HCM patients were genotyped for the presence of a benign mutation. DNA was obtained after informed consent; specific MHY7, TNNT2, and TPM1 fragments were amplified by polymerase chain reaction; and the mutations were detected by denaturing high-performance liquid chromatography and automated DNA sequencing. Only 5 (1.7%) of the 293 patients possessed a benign mutation. Moreover, all 5 subjects with an ascribed benign mutation had already manifested clinically severe expression of HCM, with all 5 requiring surgical myectomy, 3 of the 5 having a family history of sudden cardiac death, and 1 adolescent requiring an orthotopic heart transplant. CONCLUSIONS: These findings demonstrate the rarity of specific mutations in HCM and challenge the notion of mutation-specific clinical outcomes. Fewer than 2% of the subjects harbored a benign mutation, and those patients with a benign mutation experienced a very serious clinical course.

Artificial membrane-binding proteins stimulate oxygenation of stem cells during engineering of large cartilage tissue.

Restricted oxygen diffusion can result in central cell necrosis in engineered tissue, a problem that is exacerbated when engineering large tissue constructs for clinical application. Here we show that pre-treating human mesenchymal stem cells (hMSCs) with synthetic membrane-active myoglobin-polymer-surfactant complexes can provide a reservoir of oxygen capable of alleviating necrosis at the centre of hyaline cartilage. This is achieved through the development of a new cell functionalization methodology based on polymer-surfactant conjugation, which allows the delivery of functional proteins to the hMSC membrane. This new approach circumvents the need for cell surface engineering using protein chimerization or genetic transfection, and we demonstrate that the surface-modified hMSCs retain their ability to proliferate and to undergo multilineage differentiation. The functionalization technology is facile, versatile and non-disruptive, and in addition to tissue oxygenation, it should have far-reaching application in a host of tissue engineering and cell-based therapies.

Dosimetric consequences of manual pullback procedure for coronary artery radiotherapy with 90Sr/90Y beta-source.

PURPOSE: This work presents a quantitative dosimetric analysis of the Novoste (90)Sr/(90)Y beta-source cardiovascular brachytherapy treatments using a manual pullback technique for patients with in-stent restenosis. METHODS AND MATERIALS: Based on our previous measurements, a model was developed to estimate the dose in the middle of the junction region for tandem irradiation expressed as fraction of prescription dose (FPD) and dosimetric overlap length (DOL) receiving more/less than a threshold dose. The overlap/gap size was measured using the digital cine images recorded during treatment and then FPD and DOL were quantified. RESULTS: Statistical analysis of 55 patients showed that the overlap size and the FPD at 2 mm radial distance were in range of 0 to 23 mm and 13-200% of prescription dose (Rx), respectively. Four gaps out of 76 pullback cases were found, but their size was at most 5 mm. CONCLUSION: Use of a 5 mm overlap avoided underdosed regions in the vast majority of the cases. These results are the first step towards an analysis of the clinical outcome of these patients.

Could it be Quetiapine-induced Peripartum Cardiomyopathy?

Peri-partum Cardiomyopathy (PPCM) is a rare and life threatening complication of pregnancy. There are only two cases registered with the World Health Organization of cases of cardiomyopathy in patients taking Quetiapine. Here we discuss an interesting case of potential Quetiapine induced cardiomyopathy.

Clinical utility and prognostic value of left atrial volume assessment by cardiovascular magnetic resonance in non-ischaemic dilated cardiomyopathy.

AIMS: Echocardiographic studies have shown that left atrial volume (LAV) predicts adverse outcome in small heart failure (HF) cohorts of mixed aetiology. However, the prognostic value of LAV in non-ischaemic dilated cardiomyopathy (DCM) is unknown. Cardiovascular magnetic resonance (CMR) allows accurate and reproducible measurement of LAV. We sought to determine the long-term prognostic significance of LAV assessed by CMR in DCM. METHODS AND RESULTS: We measured LAV indexed to body surface area (LAVi) in 483 consecutive DCM patients referred for CMR. Patients were prospectively followed up for a primary endpoint of all-cause mortality or cardiac transplantation. During a median follow-up of 5.3 years, 75 patients died and 9 underwent cardiac transplantation. After adjustment for established risk factors, LAVi was an independent predictor of the primary endpoint [hazard ratio (HR) per 10 mL/m(2) 1.08; 95% confidence interval (CI) 1.01-1.15; P = 0.022]. LAVi was also independently associated with the secondary composite endpoints of cardiovascular mortality or cardiac transplantation (HR per 10 mL/m(2) 1.11; 95% CI 1.04-1.19; P = 0.003), and HF death, HF hospitalization, or cardiac transplantation (HR per 10 mL/m(2) 1.11; 95% CI 1.04-1.18; P = 0.001). The optimal LAVi cut-off value for predicting the primary endpoint was 72 mL/m(2). Patients with LAVi >72 mL/m(2) had a three-fold elevated risk of death or transplantation (HR 3.00; 95% CI 1.92-4.70; P < 0.001). LAVi provided incremental prognostic value for the prediction of transplant-free survival (net reclassification improvement 0.17; 95% CI 0.05-0.29; P = 0.002). CONCLUSIONS: LAVi is a powerful independent predictor of transplant-free survival and HF outcomes in DCM. Assessment of LAV improves risk stratification in DCM and should be incorporated into routine CMR examination.

Optimizing secondary prevention: Statin prescribing across East and West London in accordance with NICE guidelines.

OBJECTIVES: Statins are a well-known primary and secondary prevention drug for cardiovascular disease and NICE guidelines have been issued to identify key indicators for their use. An audit looking into statin prescribing for medical inpatients was carried out in two geographically distinct London hospitals. DESIGN: A prospective inpatient audit of medical prescription charts was performed. Blood results were reviewed for the inpatients during their admission to identify any contraindications for statin usage (rhabdomyolysis). The medical notes were also reviewed for patient refusal of statin therapy. SETTING: The study was carried out at two distinct hospitals in London. Whipps Cross University Hospital (WCUH) and Chelsea & Westminster Hospital (CWH) are located in East London and West London, respectively. Acute medical, surgical, obstetrics and gynaecology, paediatric and palliative wards were excluded. PARTICIPANTS: A total of 309 inpatient medical notes and prescription chart data were collected from WCUH (n = 211) and CWH (n = 98). MAIN OUTCOME MEASURES: High percentage of hospitalized patients are not prescribed statins despite clear clinical indications for their use. Regardless of geographical and socioeconomic factors between hospitals, statin prescribing remains suboptimal. RESULTS: The patient demographics in both hospitals were very similar; the mean age at WCUH was 78 ± 15 1SD while at CWH the mean age was 74 ± 15 1SD. The results showed that approximately one-third of patients (30% at WCUH and 33% at CWH) had at least one indication for statin therapy according to NICE guidelines and yet they were not prescribed a statin. Ten percent of patients at WCUH and 13% of patients at CWH had ischaemic heart disease (IHD) and yet were not prescribed statins. CONCLUSION: Statin prescription is often overlooked in secondary care with patients being discharged without the appropriate assessment (NICE guidelines), which subsequently means repeat prescriptions are not provided by the GP. This study is the first to show that this problem is not due to resources or geography, but is inherent within the NHS system. Consequently, a revised prescription chart checking system has been suggested for pharmacists and junior doctors.