Gene therapy on demand: Site specific regulation of gene therapy

Since 1990 when the first clinical gene therapy trial was conducted, much attention and considerable promise have been given to this form of treatment. Gene therapy has been used with success in patients suffering from severe combined immunodeficiency syndromes (X-SCID and ADA-deficiency), Leber's congenital amaurosis, hemophilia, β-thalassemia and adrenoleukodystrophy. Last year, the first therapeutic vector (Glybera) for treatment of lipoprotein lipase deficiency has been registered in the European Union. Nevertheless, there are still several numerous issues that need to be improved to make this technique more safe, effective and easily accessible for patients.     

Additional comments on migraine therapy

The symptoms and clinical management of alcohol, barbiturate and benzodiazepine withdrawal syndromes are discussed in this article. People who suffer alcohol withdrawal should be admitted to hospital if they have medical or surgical complications or severe symptoms; supportive care and pharmacotherapy, especially diazepam loading, are the essential components of treatment. Barbiturate withdrawal requires pharmacotherapy and admission to hospital for patients who have taken more than 0.4 g/d of secobarbital or an equivalent amount of another barbiturate for 90 days or longer, or 0.6 g/d or an equivalent dose for 30 days or longer, or who have had withdrawal seizures or delirium; phenobarbital loading is recommended. Regular benzodiazepine therapy that has lasted at least 3 months should be gradually stopped. Short-acting agents should be replaced with long-acting ones, such as diazepam, to avoid withdrawal symptoms. Most of these patients can be managed on an outpatient basis.     

Cancer therapy design based on pathway logic

MOTIVATION: Cancer encompasses various diseases associated with loss of cell cycle control, leading to uncontrolled cell proliferation and/or reduced apoptosis. Cancer is usually caused by malfunction(s) in the cellular signaling pathways. Malfunctions occur in different ways and at different locations in a pathway. Consequently, therapy design should first identify the location and type of malfunction to arrive at a suitable drug combination. RESULTS: We consider the growth factor (GF) signaling pathways, widely studied in the context of cancer. Interactions between different pathway components are modeled using Boolean logic gates. All possible single malfunctions in the resulting circuit are enumerated and responses of the different malfunctioning circuits to a 'test' input are used to group the malfunctions into classes. Effects of different drugs, targeting different parts of the Boolean circuit, are taken into account in deciding drug efficacy, thereby mapping each malfunction to an appropriate set of drugs.     

Bridging therapy for early surgery in patients on dual antiplatelet therapy after drug-eluting stent implantation

Objectives

To evaluate stent-related adverse cardiac events and bleeding complications within 30 days after surgical procedures in patients with recent drug-eluting stent (DES) implantation, in whom a bridging protocol was used.

Methods

In our centre a bridging protocol is used in patients scheduled for cardiac or non-cardiac surgery within 6 months after PCI with DES implantation. Clopidogrel and in some cases also acetylsalicylic acid is discontinued 5 days prior to the planned intervention and patients are admitted 2 to 3 days before the intervention for tirofiban infusion. This is discontinued 4 h before intervention. Close postoperative monitoring is performed and double antiplatelet therapy is restarted as soon as possible. Thirty-six consecutive patients were included in the protocol, 15 receiving coronary artery bypass graft and 21 non-cardiac interventions. Thrombotic and bleeding complications were studied for up to 30 days after the bridged procedure.

Results

No incidences of stent thrombosis or other adverse cardiac events (mortality, myocardial infarction) were seen in up to 30 days of follow-up. However, 6 bleeding events were reported of which 5 required a blood transfusion.

Conclusion

Our bridging protocol in patients requiring surgery after recent PCI with DES seems adequate to prevent stent thrombosis in this high-risk group. The bleeding risk is not insignificant but in our patient group controllable without major late sequelae. Larger studies should be performed to establish safety and efficacy in order to develop guidelines for these patients.     

Effects of CCNU therapy on human chromosomes

Peripheral blood lymphocytes of 9 patients under CCNU therapy were examined for frequency of sister-chromatid exchanges (SCEs) and chromosomal aberrations (CAs). 7 out of 9 patients were treated with only CCNU, whereas the remaining 2 were treated with other chemotherapeutic agents in combination with CCNU. Compared to normal individuals, a significantly increased frequency of SCE was observed in the patients before starting anticancer therapy (P less than 0.001). Increased incidences of structural changes in chromosomes were observed in cells from all the treated patients. The most frequent aberrations were of chromatid type. After administration of a single dose of CCNU, an increase in SCE frequencies was observed which remained elevated even after 6 weeks. It was concluded that increases in SCEs and CAs in lymphocytes were caused by CCNU treatment. Further studies are needed to elucidate whether any CAs observed in the present study could participate in the induction of second neoplasm.     

Effect of magnetic therapy on selected physical performances

The purpose of this study was to investigate the effects of magnetic therapy in the form of shoe insoles on vertical jump, bench squat, 40-yd dash, and a soccer-specific fitness test performance. Subjects were 14 collegiate male soccer players who were pretested, retested 3 weeks later, and then placed into a double-blind control or treatment group using a matching procedure. The control group received magnetic shoe insoles with a rating of 125 gauss, and the treatment group received insoles with a rating of 600 gauss. Subjects wore the insoles during practice and games for 7 weeks and were then retested. Results indicated significant differences among test scores during the 3 time periods but not between the treatment and control groups. There was a decline in 40-yd dash performance from the initial evaluation (5.10 seconds) to the final evaluation (5.08 seconds). There were no other significant differences. Within the limitations of the study, magnetic therapy did not improve physical performance.     

Effect of antibiotic therapy and vaccine therapy on the phagocytic reaction in mice infected with Staphylococcus

The time course of changes in the activity, intensity and completeness of phagocytosis with leukocytes of the peritoneal exudate was studied on mice with experimental staphylococcal infection treated with rifampicin, lincomycin and inactivated staphylococcal vaccine used alone or in combination. It was shown that immunization of the animals with inactivated staphylococcal vaccine promoted stimulation of the phagocytic defense. Rifampicin and lincomycin applied therapeutically induced a decrease in the activity, intensity and completeness of phagocytosis. It should be noted that rifampicin had a less pronounced inhibitory effect than lincomycin. The combined use of vaccine and antibiotics with therapeutic purposes promoted an increase in phagocytosis as compared to the use of the antibiotics alone. The combined therapy sometimes resulted in completeness of phagocytosis making it reach the control values (the 10th and 15th days, rifampicin and vaccine). It should be noted that a more pronounced stimulation of the activity, intensity and completeness of the phagocytosis was observed with the use of the combination of rifampicin and the vaccine.     

Cardiotonic steroids on the road to anti-cancer therapy

The sodium pump, Na(+)/K(+)-ATPase, could be an important target for the development of anti-cancer drugs as it serves as a versatile signal transducer, it is a key player in cell adhesion and its aberrant expression and activity are implicated in the development and progression of different cancers. Cardiotonic steroids, known ligands of the sodium pump have been widely used for the treatment of heart failure. However, early epidemiological evaluations and subsequent demonstration of anti-cancer activity in vitro and in vivo have indicated the possibility of developing this class of compound as chemotherapeutic agents in oncology. Their development to date as anti-cancer agents has however been impaired by a narrow therapeutic margin resulting from their potential to induce cardiovascular side-effects. The review will thus discuss (i) sodium pump structure, function, expression in diverse cancers and its chemical targeting and that of its sub-units, (ii) reported in vitro and in vivo anti-cancer activity of cardiotonic steroids, (iii) managing the toxicity of these compounds and the limitations of existing preclinical models to adequately predict the cardiotoxic potential of new molecules in man and (iv) the potential of chemical modification to reduce the cardiovascular side-effects and improve the anti-cancer activity of new molecules.     

Influence of cholesterol on cancer progression and therapy

Cholesterol is a fundamental molecule necessary for the maintenance of cell structure and is vital to various normal biological functions. It is a key factor in lifestyle-related diseases including obesity, diabetes, cardiovascular disease, and cancer. Owing to its altered serum chemistry status under pathological states, it is now being investigated to unravel the mechanism by which it triggers various health complications. Numerous clinical studies in cancer patients indicate an alteration in blood cholesterol level (either decreased or increased) in comparison to normal healthy individuals. This article elaborates on our understanding as to how cholesterol is being hijacked in the malignancy for the development, survival, stemness, progression, and metastasis of cancerous cells. Also, it provides a glimpse of how cholesterol derived entities, alters the signaling pathway towards their advantage. Moreover, deregulation of the cholesterol metabolism pathway has been often reported to hamper various treatment strategies in different cancer. In this context, attempts have been made to bring forth its relevance in being targeted, in pre-clinical and clinical studies for various treatment modalities. Thus, understanding the role of cholesterol and deciphering associated molecular mechanisms in cancer progression and therapy are of relevance towards improvement in the management of various cancers.     

Getting TRAIL back on track for cancer therapy

Unlike other members of the TNF superfamily, the TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo2L) possesses the unique capacity to induce apoptosis selectively in cancer cells in vitro and in vivo. This exciting discovery provided the basis for the development of TRAIL-receptor agonists (TRAs), which have demonstrated robust anticancer activity in a number of preclinical studies. Subsequently initiated clinical trials testing TRAs demonstrated, on the one hand, broad tolerability but revealed, on the other, that therapeutic benefit was rather limited. Several factors that are likely to account for TRAs'' sobering clinical performance have since been identified. First, because of initial concerns over potential hepatotoxicity, TRAs with relatively weak agonistic activity were selected to enter clinical trials. Second, although TRAIL can induce apoptosis in several cancer cell lines, it has now emerged that many others, and importantly, most primary cancer cells are resistant to TRAIL monotherapy. Third, so far patients enrolled in TRA-employing clinical trials were not selected for likelihood of benefitting from a TRA-comprising therapy on the basis of a valid(ated) biomarker. This review summarizes and discusses the results achieved so far in TRA-employing clinical trials in the light of these three shortcomings. By integrating recent insight on apoptotic and non-apoptotic TRAIL signaling in cancer cells, we propose approaches to introduce novel, revised TRAIL-based therapeutic concepts into the cancer clinic. These include (i) the use of recently developed highly active TRAs, (ii) the addition of efficient, but cancer-cell-selective TRAIL-sensitizing agents to overcome TRAIL resistance and (iii) employing proteomic profiling to uncover resistance mechanisms. We envisage that this shall enable the design of effective TRA-comprising therapeutic concepts for individual cancer patients in the future.