Androgen receptor down-regulation in prostate cancer with phosphorodiamidate morpholino antisense oligomers

PURPOSE: Androgen receptor (AR) has a pivotal role in the growth and proliferation of prostate cancer (PCa). Even in advanced stages of PCa AR continues to be expressed and appears to be functional. Since the mechanisms of AR activation in androgen independent PCa have yet to be clearly defined, the decrease in AR protein by antisense compounds is an attractive therapeutic option. In this study we evaluated a novel antisense phosphorodiamidate morpholino oligomer (PMO) targeting the translational start site of AR mRNA in vitro and in vivo in a PCa xenograft and murine prostate. MATERIALS AND METHODS: AR antisense PMOs targeting the AR initiation AUG were tested in vitro and in LNCaP cells, and in vivo in LAPC-4 xenografts and normal mouse prostate. Effects on AR protein and PSA expression were assessed. RESULTS: AR antisense PMOs specifically down-regulated AR protein levels in a plasmid based screening system and also decreased endogenous AR levels in androgen responsive LNCaP cells in culture compared to control nonspecific PMOs. Pretreatment and posttreatment biopsies in the LAPC-4 xenograft model demonstrated that the antisense AR PMO administered intraperitoneally specifically decreased AR protein levels and serum PSA. Analysis of tissue distribution of the AR PMO by high performance liquid chromatography based methodology showed significant PMO levels in tumor tissue and mouse prostate, and there was a dose dependent decrease in AR protein levels in murine AR antisense PMO treated mouse prostates. CONCLUSIONS: An AR antisense PMO with unique chemical properties administered once daily can decrease AR protein levels and PSA in vivo. The reduction of AR protein with an antisense PMO may be an effective method of interfering with AR mediated growth in advanced human PCa.     

A Comparison of the LigaSure and Harmonic Scalpel in Thyroid Surgery: A Single Institution Review

Background

During the last few years, many surgeons have begun to utilize the LigaSure device or Harmonic scalpel to perform thyroid surgery. Several papers have demonstrated the benefits of these devices compared with traditional hand-tying techniques. The purpose of this study was to examine our institution’s experience with the LigaSure device and Harmonic scalpel during thyroid surgery and to compare mean operative times and complications associated with each device.

Methods

A retrospective chart review was performed on all patients who underwent thyroid surgery using the LigaSure device or Harmonic scalpel at a single institution between December 2005 and August 2009. Charts were reviewed for patient demographics, mean operative time, length of stay, and complications, such as transient recurrent laryngeal nerve injury, hypocalcemia, and hematoma formation.

Results

A total of 231 patients were included in the study, of whom 123 underwent total thyroidectomy and 108 underwent lobectomy. There was a significant decrease in the operative time for both thyroidectomies and lobectomies when the Harmonic scalpel was utilized. In regard to complications, there was no statistically significant difference in the number of transient and permanent recurrent laryngeal nerve injuries, percentage of patients developing hypocalcemia, or rate of hematoma development.

Conclusion

In this study, there was no difference in the rate of complications between the two devices. However, the use of the Harmonic scalpel significantly decreased operative time for both thyroidectomies and thyroid lobectomies compared with the LigaSure device.     

Acidente vascular cerebral no perioperatório após ressecção transuretral de próstata: alto índice de suspeita e estabilização de parâmetros fisiológicos podem salvar vidas

We report a case of a 72 year old hypertensive male who developed severe hypertension followed by neurological deterioration in the immediate postoperative period after transurethral resection of prostate. While arterial blood gas and laboratory tests excluded transurethral resection of prostate syndrome or any other metabolic cause, reduction of blood pressure failed to ameliorate the symptoms. A cranial CT done 4 hours after the onset of neurological symptoms revealed bilateral gangliocapsular and right thalamic infarcts. Oral aspirin was advised to prevent early recurrent stroke. Supportive treatment and mechanical ventilation ensured physiological stability and the patient recovered completely over the next few days without any residual neurological deficit.     

Novel and recurrent germline LEMD3 mutations causing Buschke–Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis

Mutations in the LEMD3 gene were recently incriminated in Buschke–Ollendorff syndrome (BOS) and osteopoikilosis, with or without melorheostosis. The relationship of this gene with isolated sporadic melorheostosis is less clear. We investigated LEMD3 in a two-generation BOS family showing an extremely variable expression of the disease, in a sporadic patient with skin features of BOS, and in an additional subject with isolated melorheostosis. We identified two different mutations, both resulting in a premature stop codon, in the two cases of BOS. The mutation (c.2564G>A) reported in the familial case is novel, while that observed in the sporadic case (c.1963C>T) has been previously reported in an American woman with osteopoikilosis and melorheostosis who had a family history of isolated osteopoikilosis. The search for mutations in DNA extracted from the peripheral blood, as well as skin and bone biopsies of the patient with melorheostosis failed to identify any pathogenic change. Our results further expand the LEMD3 mutation repertoire, corroborate the extreme interfamilial and intrafamilial clinical variability of LEMD3 mutations, and underline the lack of a clear phenotype–genotype correlation in BOS. The present study supports the general conclusion that LEMD3 mutations do not contribute to isolated sporadic melorheostosis. The genetic or epigenetic influences that are responsible for the development of melorheostosis require further investigation.     

Oxidative stress and intracellular pH in the young and old erythrocytes of rat

The effects of oxidative stress (OS) on the rat erythrocytes (RBCs) that were fractionated on the percoll/BSA gradient into young and old cells were studied to find out if the altered Na ⁺ /H⁺ and Cl⁻/HCO₃ ⁻ antiporters and in turn the intracellular pH (pH_i) could act as one of the promoters of cell death. Old cells were more spherical with lesser surface area, more fragile osmotically and had lesser protein sulphydryl content than the young cells. OS was induced in RBCs by 2,2′-azobis (2-amidinopropane) dihydrochloride (AAPH). AAPH increased the superoxide dismutase (SOD) activity and MDA level and, the changes between the young and old. Interestingly, vitamin C was effective in reducing MDA in the old. Further, in the old a rapid Na⁺-dependent acidification in the presence of AAPH and a marginal acidosis in the presence of vitamin C were evident. Old RBCs exhibited higher acidosis and vitamin C was less effective in lowering the stress-induced acidosis compared to the young. Our studies suggest that increased acidosis followed by low intracellular pH could be one of the determinant factors for the disappearance of old RBCs from circulation, and perhaps of the young too under OS.     

Insulin-like growth factor binding protein-3 induces early apoptosis in malignant prostate cancer cells and inhibits tumor formation in vivo

BACKGROUND: Insulin-like growth factor binding protein (IGFBP-3) levels are significantly reduced in malignant prostate epithelial cells. In this study, we evaluated the role of endogenous IGFBP-3 on prostate cancer cell growth and tumorigenesis. METHODS: IGFBP-3 was re-expressed by stable transfection of human IGFBP-3 cDNA in a model of human prostate cancer, M12, a malignant subline in which IGFBP-3 levels are undetectable in comparison to the parent epithelial cell, P69. Effect of IGFBP-3 re-expression (M12-BP-3) on growth kinetics, morphology, propensity to apoptosis, and in vivo tumor formation were studied. RESULTS: M12-BP-3 cells secreted IGFBP-3 and growth arrested at a cell density that was threefold lower than control cells and this was associated with marked alteration in cell morphology. Control cells when grown in conditioned media secreted by M12-BP-3 also showed altered morphology compared to when cultured in IGFBP-3-immunodepleted conditioned media. The M12-BP-3 clones showed altered mitochondrial membrane potential, increased PARP cleavage, increase in sub-G1 peak, decreased levels of neuron specific enolase, and decreased tumor formation in athymic, nude mice. CONCLUSIONS: These data suggest that IGFBP-3 induces early apoptosis and has potential tumor suppressive effect in prostate cancer. Prostate 51: 141-152, 2002.     

Solitary pulmonary metastasis from intracranial meningiothelial meningioma

Although known, histologically proven pulmonary metastasis from a benign intracranial meningioma is exceedingly rare. We report a case of meningiothelial meningioma producing a solitary pulmonary deposit.