A novel direction modulated brachytherapy technique for urethra sparing in high-dose-rate brachytherapy of prostate cancer.

PURPOSE: Image-guided high-dose-rate (HDR) prostate brachytherapy is a safe and effective treatment option for prostate cancer patients; however, some patients still experience acute and late genitourinary (GU) toxicity. Studies have shown that urethral dose is associated with the incidence and severity of GU toxicity. Therefore, a technique that can further spare the urethra while ensuring adequate target coverage is highly desirable. Intensity modulated brachytherapy (IMBT) designs, such as rotating shield brachytherapy (RSBT), offer ideal dosimetry theoretically but are challenging to implement clinically due to the need for high precision in moving the treatment delivery mechanisms synchronized with the source loading. In this study, we propose a novel relatively easy-to-implement solution based on the direction modulated brachytherapy (DMBT) design concept, which does not involve moving parts and works effectively with the ubiquitous 192Ir source. MATERIALS AND METHODS: The popular Varian VS2000 (VS) and GammaMedPlus (GMP) 192Ir sources, with outer diameters of 0.6 mm and 0.9 mm, respectively, were simulated using the GEANT4 Monte Carlo (MC) simulation code. The novel DMBT needle concept consists of a 14-gauge nitinol needle, which houses a platinum shield inside. A single groove, consistent with the outer diameter of each source, was incorporated inside the platinum shield to accommodate the HDR source. The maximum thickness of the shield was 1.1 mm (0.8 mm) for the VS (GMP) source. To evaluate the effectiveness of the DMBT needle concept in reducing urethral dose, 6 patient cases were studied and DMBT plans were created by replacing two needles close to the urethra with the DMBT needles. The dosimetric comparisons between the DMBT and reference clinical plans were done by assessing the dose-volume histogram (DVH) planning criteria for the target coverage and organs-at-risk. RESULTS: The MC results showed that the use of the novel DMBT needle design with the VS source (GMP source) could reduce the dose by 49.6% (39.2%) at 1 cm from the needle behind the platinum shield, as compared to the unshielded side. Additionally, when using the same DVH planning criteria as the original plan, the DMBT plan with the VS (GMP) source reduced the maximum urethral dose by 10.3% ± 5.6% (8.1% ± 5.0%) and 17.7% ± 14.2% (16.6% ± 13.3%) for 0 mm and 2 mm margins, respectively, while maintaining equivalent V90% and D100 target coverage. CONCLUSION: The novel DMBT technique offers a promising clinically implementable solution for sparing urethra, particularly in pre-apical region, without compromising the target coverage or increasing treatment time.

Effective Gene Silencing Mediated by Polypeptide Nanoparticles LAH4-L1-siMDR1 in Multi-Drug Resistant Human Breast Cancer.

MDR (multi-drug resistance) is a major obstacle to the successful treatment of cancers. The combination therapeutic based on RNAi has been investigated as a potential strategy for reversing the MDR. However, the effective delivery of siRNA in vivo remains the challenge for the reality of these candidate RNAi drugs. Cationic peptides for gene delivery have attracted considerable attention due to their biocompatibility and high safety. Herein, self-assembled polypeptide nanoparticles LAH4-L1-siRNA (PNLS) were prepared and loaded with a siRNA (siMDR1) for overcoming MDR in human breast cancer MCF-7/ADR cells in vitro and in vivo. Owing to its cationic charges and α-helical conformation, the histidinerich peptide enhanced cellular uptake of siRNA and represented high gene silencing efficiency. The cellular uptake pathways and internalization process of PNLS into cells were further investigated. In vivo biodistribution indicated that the PNLS exhibited higher tumor-targeted delivery. More importantly, PNLS combined with PTX (Paclitaxel) showed antitumor effects and high MDR1 gene silencing efficiency in the tumor-bearing nude mice. Overall, the PNLS achieved the genetargeted knockdown in vivo and hold immense promise for a new therapeutic drug for breast cancer treatment.

SIRT1 protects against myocardial ischemia-reperfusion injury via activating eNOS in diabetic rats.

BACKGROUND: Diabetic patients are more sensitive to myocardial ischemic injury than non-diabetic patients. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase making the heart more resistant to ischemic injury. As SIRT1 expression is considered to be reduced in diabetic heart, we therefore hypothesized that up-regulation of SIRT1 in the diabetic heart may overcome its increased susceptibility to ischemic injury. METHODS: Male Sprague-Dawley rats were fed with high-fat diet and injected with streptozotocin once to induce diabetes. Diabetic rats received injections of adenoviral vectors encoding SIRT1 (Ad-SIRT1) at five myocardial sites. Four days after adenoviral injection, the rats were subjected to myocardial ischemia and reperfusion (MI/R). Outcome measures included left ventricular function, infarct size, cellular death and oxidative stress. RESULTS: Delivery of Ad-SIRT1 into the hearts of diabetic rats markedly increased SIRT1 expression. Up-regulation of SIRT1 in diabetic hearts improved cardiac function and reduced infarct size to the extent as in non-diabetic animals following MI/R, which was associated with reduced serum creatine kinase-MB, lactate dehydrogenase activities and cardiomyocyte apoptosis. Moreover, Ad-SIRT1 reduced the increase in the superoxide generation and malonaldialdehyde content and simultaneously increased the antioxidant capability. Furthermore, Ad-SIRT1 increased eNOS phosphorylation and reduced eNOS acetylation in diabetic hearts. NOS inhibitor L-NAME inhibited SIRT1-enhanced eNOS phosphorylation, and blunted SIRT1-mediated anti-apoptotic and anti-oxidative effects and cardioprotection. CONCLUSIONS: Overexpression of SIRT1 reduces diabetes-exacerbated MI/R injury and oxidative stress via activating eNOS in diabetic rats. The findings suggest SIRT1 may be a promising novel therapeutic target for diabetic cardiac complications.

Calorie Restriction Attenuates Monocrotaline-induced Pulmonary Arterial Hypertension in Rats.

Calorie restriction (CR) is one of the most effective nonpharmacological interventions protecting against cardiovascular disease, such as hypertension in the systemic circulation. However, whether CR could attenuate pulmonary arterial hypertension (PAH) is largely unknown. The PAH model was developed by subjecting the rats to a single subcutaneous injection of monocrotaline. CR lowered mean pulmonary arterial pressure (mPAP) and reduced vascular remodeling and right ventricular hypertrophy in PAH rats. Meanwhile, CR attenuated endothelial dysfunction as evidenced by increased relaxation in response to acetylcholine. The beneficial effects of CR were associated with restored sirtuin-1 (SIRT1) expression and endothelial nitric oxide synthase (eNOS) phosphorylation and reduced eNOS acetylation in pulmonary arteries of PAH rats. To further clarify the role of SIRT1 in the protective effects of CR, adenoviral vectors for overexpression of SIRT1 were administered intratracheally at 1 day before monocrotaline injection. Overexpression of SIRT1 exhibited similar beneficial effects on mPAP and endothelial function, and increased eNOS phosphorylation and reduced eNOS acetylation in the absence of CR. Moreover, SIRT1 overexpression attenuated the increase in mPAP in hypoxia-induced PAH animals. Overall, the present data demonstrate that CR may serve as an effective treatment of PAH, and targeting the SIRT1/eNOS pathway may improve treatment of PAH.