Targeting of small molecule anticancer drugs to the tumour and its vasculature using cationic liposomes: lessons from gene therapy

Cationic (positively charged) liposomes have been tested in various gene therapy clinical trials for neoplastic and other diseases. They have demonstrated selectivity for tumour vascular endothelial cells raising hopes for both antiangiogenic and antivascular therapies. They are also capable of being selectively delivered to the lungs and liver when administered intravenously. These vesicles are being targeted to the tumour in various parts of the body by using advanced liposomal systems such as ligand-receptor and antibody-antigen combinations. At present, the transferrin receptor is commonly used for cancer-targeted drug delivery systems including cationic liposomes. This review looks at the growing utility of these vesicles for delivery of small molecule anticancer drugs.     

Occurrence of<Emphasis Type="Italic">Fusarium</Emphasis> toxins in the 1999’s harvest

Continuing the monitoring ofFusarium toxins in cereals, we investigated 245 samples of wheat, barley, triticale and oats in 1999. 84 samples out of 100 analysed forFusarium could be found to be infected. The most prominentFusarium species detected whereF. avenaceum, F. poae, F. detected whereF. avenaceum, F. poae, F. graminearum, andF. sporotrichoides. The level of mycotoxin contamination of the samples varied depending on their origins and was in general very low in comparison with the result obtained in samples of the previous year. There where only some wheat samples with deoxynivalenol (DON) concentrations beyond existing advisory levels. The average DON concentration of all samples was 0.35 mg/kg with a median of 0.007 mg/kg. 3-Acetyldeoxynivalenol and zearalenone (ZEA) could only be detected at minor concentrations (below 0.1 and 0.05 mg/kg, respectively) in less than 10% of the samples. The analysis of commercial cereal flour reflects this situation. Flour bought in the first quarter of 1999, which was suspected to contain a high portion of the 1998 harvest, was contaminated by DON to a higher extent than those purchased in 2000. The average DON concentration in the flour samples of 1999 and 2000 was 0.35 mg/kg and 0.23 mg/kg, respectively. Although the general mycotoxin level in the 1999 harvest was lower as in 1998 there were some highly contaminated samples that had mainly been grown in fields with either maize or other cereals as previous crop and reduced tillage. The combination of maize as previous crop and non-tillage could be stated as most unsuitable, which promotes enhanced mycotoxin contamination, and should therefore be avoided.     

The role of thallium-201 and pentavalent dimercaptosuccinic acid for staging cartilaginous tumours

INTRODUCTION: Heterogeneity of cartilage tumours may confound accurate diagnosis and grading resulting in under and over treatment. Improved preoperative assessment of malignancy and grade would be invaluable for developing a rational plan for treatment. We examined correlations between nuclear tracer avidity and malignancy grade in cartilage tumours. METHODS: Between 1996 and 2000, 92 consecutive patients with cartilaginous tumours (50 benign, 42 non-metastatic malignant) underwent nuclear scanning. Thallium-201 (TL-201) and pentavalent dimercaptosuccinic acid (DMSAV) were used as nuclear isotopes. Scanning with these agents was performed on separate days 48 hours apart. Static and SPECT images were obtained at 30 m and 4 h after injection of nuclear tracer. Pathology review was undertaken blinded to the results of the nuclear scans and correlations between histologic results and trace uptake at 4 hours examined. RESULTS: 25 patients with negative DMSAV had benign tumours. 15/17 tumours with positive TL-201 had malignant tumours. 11/13 patients with both positive DMSAV and TL-201 scans had intermediate or high grade tumours and 4 of these developed metastases. We have developed an algorithm for the management of patients with tumours that aims to avoid over treatment of low grade tumours and under treatment of high grade tumours. CONCLUSION: Functional nuclear scanning with TL-201 and DMSAV complements other imaging modalities in the management of cartilaginous tumours.     

Autophagy and genomic integrity

DNA lesions, constantly produced by endogenous and exogenous sources, activate the DNA damage response (DDR), which involves detection, signaling and repair of the damage. Autophagy, a lysosome-dependent degradation pathway that is activated by stressful situations such as starvation and oxidative stress, regulates cell fate after DNA damage and also has a pivotal role in the maintenance of nuclear and mitochondrial genomic integrity. Here, we review important evidence regarding the role played by autophagy in preventing genomic instability and tumorigenesis, as well as in micronuclei degradation. Several pathways governing autophagy activation after DNA injury and the influence of autophagy upon the processing of genomic lesions are also discussed herein. In this line, the mechanisms by which several proteins participate in both DDR and autophagy, and the importance of this crosstalk in cancer and neurodegeneration will be presented in an integrated fashion. At last, we present a hypothetical model of the role played by autophagy in dictating cell fate after genotoxic stress.     

Associations between COPD related manifestations: a cross-sectional study

Background

Cardiovascular disease, osteoporosis and emphysema are associated with COPD. Associations between these factors and whether they predict all-cause mortality in COPD patients are not well understood. Therefore, we examined associations between markers of cardiovascular disease (coronary artery calcification [CAC], thoracic aortic calcification [TAC] and arterial stiffness), bone density (bone attenuation of the thoracic vertebrae), emphysema (PI-950 and 15th percentile) and all-cause mortality in a COPD cohort.

Methods

We assessed CAC, TAC, bone attenuation of the thoracic vertebrae, PI-950 and 15th percentile on low-dose chest computed tomography in COPD subjects. We measured arterial stiffness as carotid-radial pulse wave velocity (PWV), and identified deaths from the national register.

Results

We studied 119 COPD subjects; aged 67.8 ±7.3, 66% were males and mean FEV₁% predicted was 46.0 ±17.5. Subjects were classified into three pre-specificed groups: CAC = 0 (n = 14), 0 < CAC ≤ 400 (n = 41) and CAC > 400 (n = 64). Subjects with higher CAC were more likely to be older (p < 0.001) and male (p = 0.03), and more likely to have higher systolic blood pressure (p = 0.001) and a history of hypertension (p = 0.002) or ischemic heart disease (p = 0.003). Higher CAC was associated with higher PWV (OR 1.62, p = 0.04) and lower bone attenuation (OR 0.32, p = 0.02), but not with 15th percentile, after adjustment for age, sex and pack-years of smoking. In a Cox proportional hazards model, CAC, TAC and 15th percentile predicted all-cause mortality (HR 2.01, 2.09 and 0.66, respectively).

Conclusions

Increased CAC was associated with increased arterial stiffness and lower bone density in a COPD cohort. In addition, CAC, TAC and extent of emphysema predicted all-cause mortality.

Trial registration

Lothian NHS Board, Lothian Research Ethics Committee, LREC/2003/8/28.     

Prediction and course of symptoms and lung function around an exacerbation in chronic obstructive pulmonary disease

Background

Frequent exacerbations induce a high burden to Chronic Obstructive Pulmonary Disease (COPD). We investigated the course of exacerbations in the published COSMIC study that investigated the effects of 1-year withdrawal of fluticasone after a 3-month run-in treatment period with salmeterol/fluticasone in patients with COPD.

Methods

In 373 patients, we evaluated diary cards for symptoms, Peak Expiratory Flow (PEF), and salbutamol use and assessed their course during exacerbations.

Results

There were 492 exacerbations in 224 patients. The level of symptoms of cough, sputum, dyspnea and nocturnal awakening steadily increased from 2 weeks prior to exacerbation, with a sharp rise during the last week. Symptoms of cough, sputum, and dyspnea reverted to baseline values at different rates (after 4, 4, and 7 weeks respectively), whereas symptoms of nocturnal awakening were still increased after eight weeks. The course of symptoms was similar around a first and second exacerbation. Increases in symptoms and salbutamol use and decreases in PEF were associated with a higher risk to develop an exacerbation, but with moderate predictive values, the areas under the receiver operating curves ranging from 0.63 to 0.70.

Conclusions

Exacerbations of COPD are associated with increased symptoms that persist for weeks and the course is very similar between a first and second exacerbation. COPD exacerbations are preceded by increased symptoms and salbutamol use and lower PEF, yet predictive values are too low to warrant daily use in clinical practice.     

Tumor Necrosis Factor-α +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease

Background  

Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory process, in which the pro-inflammatory cytokine Tumor Necrosis Factor (TNF)-α is considered to play a role. In the present study the putative involvement of TNF-α gene polymorphisms in pathogenesis of COPD was studied by analysis of four TNF-α gene polymorphisms in a Caucasian COPD population.     

Durable remissions are rare following high dose therapy with autologous stem cell transplantation for adults with "paediatric" bone and soft tissue sarcomas

BACKGROUND: The role of high dose therapy (HDT) with autologous stem cell transplantation (AuSCT) for the treatment of bone and soft tissue sarcomas remains investigational. There are few reports examining this strategy focusing on the adult population. METHODS: We retrospectively reviewed our experience of adult patients undergoing HDT and AuSCT for 'paediatric' sarcomas. RESULTS: A total of 17 patients (14 male, 3 female) with median age at transplant of 24 years (range 20 - 41) were identified. The diagnosis was Ewings sarcoma/PNET (10), osteosarcoma (5) and rhabdomyosarcoma (2). Status prior to HDT, following conventional-dose chemotherapy +/- surgery +/- radiotherapy, was complete remission (CR) (6), partial remission (PR) (6), stable disease (1) and progressive disease (4). There was no transplant-related mortality. Two patients remain disease free beyond four years and both received HDT as part of their primary therapy (CR1 and PR1) however, the median progression free survival and overall survival following AuSCT for the entire cohort was only 7 months (range: 2-92 months) and 13 months (range: 2 - 92 months), respectively. CONCLUSION: HDT and AuSCT infrequently achieves prolonged remissions in adult patients and should only be considered in patients who are in a PR or CR following conventional-dose therapy. Further studies are required to define the role of HDT with AuSCT for adult patients with sarcoma.     

Using wintergreen oil for mounting mosquito larvae: a safer alternative to xylene

Permanent mounting of fourth instar mosquito larvae is essential for identifying Aedes spp. This procedure requires extensive exposure to xylene, a clearing agent in the mounting process. We investigated wintergreen oil as a substitute for xylene. Five hundred larvae were mounted on slides to evaluate shrinkage or expansion of specimens after clearing using xylene or wintergreen oil. We examined the ventral brush and siphonal hair tufts for species identification and for preservation of morphological characteristics after clearing specimens in xylene or wintergreen oil. Shrinkage of the length of whole larvae and width of the head, thorax and abdomen after mounting was significantly greater after clearing with xylene than with wintergreen oil. The length of the comb scale nearest the ventral brush was similar for both clearing agents. The clarity of the specimens after mounting was improved by clearing with wintergreen oil, but the integrity of the ventral brush and siphonal hair tufts were similar for both clearing agents.