Sourcing of an Alternative Pericyte-Like Cell Type from Peripheral Blood in Clinically Relevant Numbers for Therapeutic Angiogenic Applications

Autologous cells hold great potential for personalized cell therapy, reducing immunological and risk of infections. However, low cell counts at harvest with subsequently long expansion times with associated cell function loss currently impede the advancement of autologous cell therapy approaches. Here, we aimed to source clinically relevant numbers of proangiogenic cells from an easy accessible cell source, namely peripheral blood. Using macromolecular crowding (MMC) as a biotechnological platform, we derived a novel cell type from peripheral blood that is generated within 5 days in large numbers (10–40 million cells per 100 ml of blood). This blood-derived angiogenic cell (BDAC) type is of monocytic origin, but exhibits pericyte markers PDGFR-β and NG2 and demonstrates strong angiogenic activity, hitherto ascribed only to MSC-like pericytes. Our findings suggest that BDACs represent an alternative pericyte-like cell population of hematopoietic origin that is involved in promoting early stages of microvasculature formation. As a proof of principle of BDAC efficacy in an ischemic disease model, BDAC injection rescued affected tissues in a murine hind limb ischemia model by accelerating and enhancing revascularization. Derived from a renewable tissue that is easy to collect, BDACs overcome current short-comings of autologous cell therapy, in particular for tissue repair strategies.     

Advances in the field of nanooncology

Nanooncology, the application of nanobiotechnology to the management of cancer, is currently the most important chapter of nanomedicine. Nanobiotechnology has refined and extended the limits of molecular diagnosis of cancer, for example, through the use of gold nanoparticles and quantum dots. Nanobiotechnology has also improved the discovery of cancer biomarkers, one such example being the sensitive detection of multiple protein biomarkers by nanobiosensors. Magnetic nanoparticles can capture circulating tumor cells in the bloodstream followed by rapid photoacoustic detection. Nanoparticles enable targeted drug delivery in cancer that increases efficacy and decreases adverse effects through reducing the dosage of anticancer drugs administered. Nanoparticulate anticancer drugs can cross some of the biological barriers and achieve therapeutic concentrations in tumor and spare the surrounding normal tissues from toxic effects. Nanoparticle constructs facilitate the delivery of various forms of energy for noninvasive thermal destruction of surgically inaccessible malignant tumors. Nanoparticle-based optical imaging of tumors as well as contrast agents to enhance detection of tumors by magnetic resonance imaging can be combined with delivery of therapeutic agents for cancer. Monoclonal antibody nanoparticle complexes are under investigation for diagnosis as well as targeted delivery of cancer therapy. Nanoparticle-based chemotherapeutic agents are already on the market, and several are in clinical trials. Personalization of cancer therapies is based on a better understanding of the disease at the molecular level, which is facilitated by nanobiotechnology. Nanobiotechnology will facilitate the combination of diagnostics with therapeutics, which is an important feature of a personalized medicine approach to cancer.     

Antiviral activity and safety of aplaviroc,a CCR5 antagonist,in combination with lopinavir/ritonavir in HIV‐infected,therapy‐naïve patients: results of the EPIC study (CCR100136)*

Background

This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral‐naïve patients harbouring R5‐ or R5X4‐tropic virus.

Methods

A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed.

Results

This study was terminated prematurely because of APL‐associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent‐to‐treat (M‐ITT) population]; of these, 133 completed the 12‐week treatment phase. The proportion of subjects in the M‐ITT population with HIV‐1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4‐tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability.

Conclusions

While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.     

In vivo monitoring of rat brain metabolites during vigabatrin treatment using localized 2D-COSY

A two-dimensional COSY-based localization sequence was designed to allow the in vivo monitoring of proton metabolites in rat brain [particularly gamma-aminobutyric acid (GABA), glutamine, taurine and myo-inositol]. The sequence incorporated OSIRIS signal localization, B1-insensitive water suppression and phase-sensitive COSY acquisition. The method was used to study the effects of the GABA-transaminase inhibitor vigabatrin on rat brain metabolite concentrations. Wistar rats were treated daily for 3 days with an oral dose of vigabatrin (200 mg/kg, n = 4). Localized COSY spectra were obtained during a 120 min acquisition from a 270 microl central brain voxel and compared with nine untreated control animals. Significant elevations were observed in GABA (267% of control, p < 0.005, Mann-Witney test), glutamine (130% of control, p < 0.005) and taurine (113% of control, p < 0.05). Changes in GABA and taurine were consistent with previous data on the action of Vigabatrin, and support a previously hypothesized link between these compounds. The increase in glutamine was more surprising and may reflect the balance between the level and/or site of GABA-transaminase inhibition and downregulation of GABA synthesis.     

Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283]

Background

Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR.

Methods/design

The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment.

Discussion

The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.     

NEED FOR PRECISE PROTOCOL IN MAGNETIC RESONANCE IMAGING OF THE POST OPERATIVE SPINE

Gadolinium enhanced Magnetic Resonance Imaging (MRI) for the evaluation of the post operative lumbo-sacral spine is a sensitive and specific imaging technique. A need for establishing a specific protocol for Failed Back Surgery Syndrome (FBSS) for use in the service hospitals is highlighted for convenience of patient management and preservation of active manpower. The MR scan of 50 patients performed over a span of six months, who complained of persistent low backache even after surgery, were retrospectively analysed. The specificity of this series using MRI in indicating the exact cause of FBSS was clocked at only 30%. The conditions diagnosed were rectifiable. The balance of the patients who could not be offered any specific diagnosis towards the cause, were being managed conservatively / placed in low medical category for a considerable period. It was noted with concern that there was non prevalence of sequence like the fast spin echo with gadolinium enhancement as a routine.KEY WORDS: Gadolinium, Magnetic Resonance Imaging, Post-operative spine