A mechanistic study of tumor-targeted corrole toxicity

HerGa is a self-assembled tumor-targeted particle that bears both tumor detection and elimination activities in a single, two-component complex (Agadjanian et al. Proc. Natl. Acad. Sci. U.S.A.2009, 106, 6105-6110). Given its multifunctionality, HerGa (composed of the fluorescent cytotoxic corrole macrocycle, S2Ga, noncovalently bound to the tumor-targeted cell penetration protein, HerPBK10) has the potential for high clinical impact, but its mechanism of cell killing remains to be elucidated, and hence is the focus of the present study. Here we show that HerGa requires HerPBK10-mediated cell entry to induce toxicity. HerGa (but not HerPBK10 or S2Ga alone) induced mitochondrial membrane potential disruption and superoxide elevation, which were both prevented by endosomolytic-deficient mutants, indicating that cytosolic exposure is necessary for corrole-mediated cell death. A novel property discovered here is that corrole fluorescence lifetime acts as a pH indicator, broadcasting the intracellular microenvironmental pH during uptake in live cells. This feature in combination with two-photon imaging shows that HerGa undergoes early endosome escape during uptake, avoiding compartments of pH < 6.5. Cytoskeletal disruption accompanied HerGa-mediated mitochondrial changes whereas oxygen scavenging reduced both events. Paclitaxel treatment indicated that HerGa uptake requires dynamic microtubules. Unexpectedly, low pH is insufficient to induce release of the corrole from HerPBK10. Altogether, these studies identify a mechanistic pathway in which early endosomal escape enables HerGa-induced superoxide generation leading to cytoskeletal and mitochondrial damage, thus triggering downstream cell death.     

A Multimode Optical Imaging System for Preclinical Applications In Vivo: Technology Development, Multiscale Imaging, and Chemotherapy Assessment

Purpose

Several established optical imaging approaches have been applied, usually in isolation, to preclinical studies; however, truly useful in vivo imaging may require a simultaneous combination of imaging modalities to examine dynamic characteristics of cells and tissues. We developed a new multimode optical imaging system designed to be application-versatile, yielding high sensitivity, and specificity molecular imaging.

Procedures

We integrated several optical imaging technologies, including fluorescence intensity, spectral, lifetime, intravital confocal, two-photon excitation, and bioluminescence, into a single system that enables functional multiscale imaging in animal models.

Results

The approach offers a comprehensive imaging platform for kinetic, quantitative, and environmental analysis of highly relevant information, with micro-to-macroscopic resolution. Applied to small animals in vivo, this provides superior monitoring of processes of interest, represented here by chemo-/nanoconstruct therapy assessment.

Conclusions

This new system is versatile and can be optimized for various applications, of which cancer detection and targeted treatment are emphasized here.     

Long term results for the ATS valve, the first open pivot valve: 182 cases

Between May 1995 and May 2004, 197 ATS valves were implanted in 182 patients: 120 males and 62 females with an average age of 58 +/- 13 years. 149 cases were for aortic valvular replacement and 48 cases were for the mitral valve. Fifteen patients had a double mitral and aortic replacement. Twelve tricuspid procedures were necessary, 17 patients underwent coronary revascularisation and 58 underwent an aortic procedure (Bentall, aortic sub-coronary, aortic cross). The in-hospital mortality (31 days) was 1.6%. The long term mortality at up to 9 years included 23 deaths. No death was attributed to the ATS valve. Nine thrombo-embolic events occurred, but six were minor. One mitral valve thrombosis was due to the voluntary cessation of anticoagulants and another was linked to a reduction in anticoagulant treatment. There were ten haemorrhagic events. They were all linked with an organic visceral lesion. Only one death was recorded. All patients received standard anticoagulant treatment with a target INR between 2.5 and 4. 155 patients were asked about the problem of valve noise. 139 (89.6%) stated that they did not notice any noise from their valves in everyday life. Conclusions The ATS valvular prosthesis is currently the only open pivot valve, fundamentally differentiating it from other valves with 2 leaflets. As a result of this, it has a very low rate of thrombo-embolic complications and a reduction in anticoagulant treatment could therefore be envisaged (Westaby, Van Nooten, Stefanidis). The haemodynamic characteristics are excellent and the ease of rotation of the leaflets allows optimal orientation. Finally, thanks to its structural characteristics, there is less leaflet closure noise and it is less perceptible than with other prostheses. It therefore offers an excellent quality of life.     

CONTROVERSIES IN THE MANAGEMENT OF BRAINSTEM CAVERNOUS ANGIOMA: REPORT OF TWO CASES

Two cases of cavernous angioma involving the medulla oblongata are presented. Both cases underwent surgical excision with excellent outcome. The use of surgery via craniectomy is contrasted with stereotactic radiosurgery in light of the known natural history of the lesions. As a result, it is suggested that surgical excision provides immediate protection from the risks of recurrent haemorrhage, establishes a tissue diagnosis, allows complete removal at the primary intervention, avoids complications of radiation-induced damage and is performed more easily in these vascular anomalies due to the presence of a capsule with surrounding gliotic tissue. Additionally, it is implied that the natural history of lesions in this region is still unclear. For these reasons, it is suggested that surgical excision should be the primary therapeutic intervention for cavernous angiomata that involve the brainstem.     

ACUTE LYMPHOBLASTIC LEUKEMIA OCCURRING AS A SECOND MALIGNANCY: Report of a Case and Review of Literature

Secondary leukemias occurring after the treatment of childhood malignancies are most often acute nonlymphoblastic leukemias. Only rarely do acute lymphoblastic leukemias (ALL) occur as second malignancies. An 18-year-old boy who developed ALL 4 years after Hodgkin's disease is described and the literature on secondary ALL is reviewed.     

Magnetic resonance imaging clarity of the Bryan, Prodisc-C, Prestige LP, and PCM cervical arthroplasty devices

STUDY DESIGN: Prospective, randomized, controlled and double-blinded study on imaging of artificial discs. OBJECTIVE: The purpose of this study is to compare postoperative imaging characteristics of the 4 currently available cervical arthroplasty devices at the level of implantation and at adjacent levels. SUMMARY OF BACKGROUND DATA: Cervical arthroplasty is being performed increasingly frequently for degenerative disc disease and, in most cases, with frank neural compression. Unlike lumbar arthroplasty, performed mainly for axial back pain, decompression of neural elements may need to be confirmed with postoperative imaging after cervical arthroplasty. METHODS: Preoperative and postoperative magnetic resonance imaging scans of 20 patients who had undergone cervical arthroplasty were assessed for imaging quality. Five cases each of the Bryan (Medtronic Sofamor Danek, Memphis, TN), Prodisc-C (Synthes Spine, Paoli, PA), Prestige LP (Medtronic Sofamor Danek), and PCM devices (Cervitech, Rockaway, NJ) were analyzed. Six blinded spinal surgeons scored twice sagittal and axial T2-weighted images using the Jarvik 4-point scale. Statistical analysis was performed comparing quality before surgery and after disc implantation at the operated and adjacent levels and between implant types. RESULTS.: Moderate intraobserver and interobserver reliability was noted. Preoperative images of patients in all implant groups had high-quality images at operative and adjacent levels. The Bryan and Prestige LP devices allowed satisfactory visualization of the canal, exit foramina, cord, and adjacent levels after arthroplasty. Visualization was significantly impaired in all PCM and Prodisc-C cases at the operated level in both the spinal canal and neural foramina. At the adjacent levels, image quality was statistically poorer in the PCM and Prodisc-C than those of Prestige LP or Bryan. CONCLUSIONS.: Postoperative visualization of neural structures and adjacent levels after cervical arthroplasty is variable among current available devices. Devices containing nontitanium metals (cobalt-chrome-molybdenum alloys in the PCM and Prodisc-C) prevent accurate postoperative assessment with magnetic resonance imaging at the surgical and adjacent levels. Titanium devices, with or without polyethylene (Bryan disc or Prestige LP), allow for satisfactory monitoring of the adjacent and operated levels. This information is crucial for any surgeon who wishes to assess adequacy of neural decompression and where monitoring of adjacent levels is desired.     

Evaluation of multiple measures of antiretroviral adherence in the Eastern European country of Georgia

Introduction

There is little information on adherence to antiretroviral therapy (ART) in the Eastern European region. This prospective study evaluated multiple measures of adherence and their association with viral suppression among HIV patients in Georgia.

Methods

A prospective cohort study enrolled 100 consecutive antiretroviral-naïve adult (age ≥18 years) patients, who were followed for three months. Adherence was assessed by medication refill and three self-report measures (an AIDS Clinical Trial Group [ACTG] tool for four-day adherence, a visual analogue scale [VAS] and a rating task for 30-day adherence). The VAS represented a line anchored by 0 and 100% corresponding to the percentage of prescribed doses taken. The rating task asked patients to rate their ability to take all medications as prescribed, with responses categorized into six levels of adherence: very poor (0%), poor (20%), fair (40%), good (60%), very good (80%) and excellent (100%). Patients with adherence of ≥95% by medication refill, ACTG and VAS, and ≥80% by rating task, were defined as adherent.

Results

Of 100 patients enrolled, eight had missing data and were excluded from analysis. Among the remaining 92 patients, the median age was 39 years, and 70% were men. Major modes of HIV acquisition were injection drug use (IDU; 47.3%) and heterosexual contact (44.1%). The proportions of adherent patients were as follows: 68% by medication refill, 90% by ACTG questionnaire, 38% by VAS and 42% by rating task. On average, four months after commencing ART, 52 (56.5%) patients had a viral load <400 copies/ml and 26 (28.3%) patients had a viral load <50 copies/ml. Of 43 persons with a history of IDU, 22 (51.2%) reached a viral load of <400 copies/ml. In multivariate analysis, only refill adherence was a statistically significant predictor of viral suppression of <400 copies/ml: the risk ratio was 1.7 (95% CI: 1.1–2.8). Refill adherence, VAS and rating task were associated with viral suppression of <50 copies/ml. Non-IDUs were twice as likely to achieve viral load <50 copies/ml compared to IDUs. Refill adherence had the largest area under the receiver-operating characteristic curve for predicting viral suppression.

Conclusions

Medication refill adherence was the strongest predictor of viral suppression. IDUs can achieve optimal virologic outcomes, but may require additional adherence support.