Androgen replacement therapy in the aging male

Beginning around age 40 years, men experience a decrease in testosterone level-referred to as "andropause"-and the pathophysiologic changes that accompany this decrease. Androgen replacement therapy, typically used for the treatment of senile hypogonadism, is evolving as a potential treatment of various other conditions related to testosterone loss, such as osteoporosis, sarcopenia, and even psychological symptoms. As with any treatment modality, certain patient factors are more predictive of success with minimal adverse effects, and consideration must be given to concomitant conditions. This article will provide a review of recent studies examining the effects of androgen supplementation and evaluate the purported benefits and potential risks of this therapy. Further research is anticipated to elucidate the most appropriate candidates, as well as other potential indications, for this treatment.     

Recent advances in liver-directed gene therapy: implications for the treatment of dyslipidemia

Somatic gene therapy for the treatment of dyslipidemia is an area of active investigation. A substantial body of data indicates that the transfer of various lipid-lowering genes to the liver is an effective method of restoring normal plasma lipids in animal models of dyslipidemia. Most studies have used adenoviral vectors because of their excellent gene-transfer efficiency. However, the first and second-generation adenoviral vectors used in these experiments are highly toxic and are associated with substantial morbidity and mortality. This article reviews current data on the properties of two novel vectors, the adeno-associated virus and the helper-dependent adenovirus that is devoid of all protein-encoding genes. Each type of vector has its advantages and drawbacks. They appear to be the most promising vectors to date for liver-directed gene transfer in the treatment of dyslipidemia.     

Shotgun proteomics of bacterial pathogens: advances,challenges and clinical implications

Mass spectrometry-based proteomics is increasingly used in analysis of bacterial pathogens. Simple experimental set-ups based on high accuracy mass spectrometry and powerful biochemical and bioinformatics tools are capable of reliably quantifying levels of several thousand bacterial proteins in a single experiment, reaching the analytical capacity to completely map whole proteomes. Here the authors present the state-of-the-art in bacterial pathogen proteomics and discuss challenges that the field is facing, especially in analysis of low abundant, modified proteins from organisms that are difficult to culture. Constant improvements in speed and sensitivity of mass spectrometers, as well as in bioinformatic and biochemical workflows will soon allow for comprehensive analysis of regulatory mechanisms of pathogenicity and enable routine application of proteomics in the clinical setting.     

Targeting cullin-RING ligases for cancer treatment: rationales,advances and therapeutic implications

New therapeutic intervention strategies for the treatment of human malignancies are always desired. Approval of bortezomib as a front-line treatment for multiple myeloma highlighted the significance of ubiquitin–proteasome system (UPS) as a promising therapeutic target. However, due to the broad impact of proteasome inhibition, deleterious side effects have been reported with bortezomib treatment. Cullin RING ligases (CRLs)-mediated ubiquitin conjugation process is responsible for the ubiquitin conjugation of 20 % cellular proteins that are designated for degradation through the UPS, most of them are critical proteins involved in cell cycle progression, signaling transduction and apoptosis. Studies have depicted the upstream NEDDylation pathway that controls the CRL activity by regulating the conjugation of an ubiquitin-like-protein NEDD8 to the cullin protein in the complex. A specific pharmaceutical inhibitor of NEDD8 activating enzyme (NAE; E1) MLN4924 was recently developed and has been promoted to Phase I clinical trials for the treatment of several human malignancies. This article summarizes the most recent understanding about the process of NEDD8 conjugation, its relevance for cancer therapy and molecular mechanisms responsible for the potent anti-tumor activity of MLN4924.     

A new approach to phenotyping disseminated tumor cells: methodological advances and clinical implications

At the time of primary therapy (surgery, systemic chemotherapy and/or radiation), disseminated tumor cells in the bone marrow can be found in almost one-third of patients with cancer of the breast, ovary, esophagus, stomach, colon, and other solid tumors. Whereas the prognostic impact of the mere presence of these cells is still a matter of debate, it has been shown that expression of tumor-associated antigens in disseminated tumor cells is linked to more aggressive disease. Therefore, further characterization of disseminated tumor cells at the protein and gene level has become increasingly important. To date, the most common detection method for disseminated tumor cells in the bone marrow is an immunocytochemical approach using cytokeratin-directed antibodies for detection of epithelial cells and the APAAP system for their visualization. We have established a new double immunofluorescence technique enabling simultaneous detection, phenotyping, and antigen quantification of disseminated tumor cells. Mononuclear cells from bone marrow are enriched by Ficoll gradient centrifugation and cytospins are prepared. Double immunofluorescence is performed using antibodies against cytokeratins 8/18/19 (mAb A45B/B3) and the uPA receptor CD87 (pAb HU277). CD87 expression is recorded by confocal laser scanning microscopy (CLSM) using fluorescence labeled latex beads as the reference; staining intensities of all the scans are then summed and quantified (extended focus). This protocol, originally designed for disseminated tumor cells in bone marrow, can also be applied to disseminated tumor cells in blood, to leukapheresis cells or to cells present in malignant ascites or other malignant effusions. The tumor cells detected may be used for gene and mRNA analyses. Furthermore, disseminated tumor cells also represent interesting targets for clinical studies on patient prognosis or prediction of therapy response as well as for specific tumor-biological therapies.     

Androgen deprivation therapy in the treatment of advanced prostate cancer

This article reviews the issues and controversies relevant to the treatment of advanced prostate cancer with androgen deprivation therapy. Initially, diethylstilbestrol was used for achieving androgen deprivation, but was replaced by luteinizing hormone-releasing hormone (LHRH). Adverse events associated with LHRH agonists include the flare phenomenon, hot flashes, loss of libido, erectile dysfunction, depression, muscle wasting, anemia, and osteoporosis. Intermittent therapy has been advocated to reduce morbidity of treatment. The addition of an antiandrogen provides maximum androgen blockade. There remains controversy regarding the timing of the addition of an antiandrogen. Secondary hormonal therapies include antiandrogens, adrenal androgen inhibitors, and estrogens.     

Melatonin in epilepsy: first results of replacement therapy and first clinical results

At a single evening dose of 5-10 mg, melatonin (MLT), the pineal gland hormone, can exert a positive effect on the frequency of epileptic attacks in children with sleep disturbances of various etiologies. We have shown that the sleep behavior can be normalized and an existing epilepsy can be favorably influenced. Pretherapeutic MLT secretion profiles can provide new information concerning the origin and treatment of these disturbances. In vitro experiments suggest that this effect might be the result of the interaction between MLT and MLT-specific receptors in the neocortex. Due to its favorable safety profile, MLT can be liberally administered in the specified doses and be considered as a useful antiepileptic drug.