Development of Novel Peptides for Mitochondrial Drug Delivery: Amino Acids Featuring Delocalized Lipophilic Cations

Purpose  

To create a new class of mitochondria-penetrating peptides (MPPs) that would facilitate drug delivery into the organelle through the inclusion of delocalized lipophilic cations (DLCs) in the peptide sequence.     

Inhibitory effect of live-attenuated Listeria Monocytogenes-based vaccines expressing MIA gene on malignant melanoma

Listeria monocytogenes(LM),a Gram-positive facultative intracellular bacterium,can be used as an effective exogenous antigen expression vector in tumor-target therapy.But for successful clinical application,it is necessary to construct attenuated LM stain that is safe yet retains the potency of LM based on the full virulent pathogen.In this study,attenuated LM and recombinants of LM expressing melanoma inhibitory activity(MIA) were constructed successfully.The median lethal dose(LD 50) and invasion efficiency of attenuated LM strains were detected.The recombinants were utilized for immunotherapy of animal model of B16F10 melanoma.The level of MIA mRNA expression in tumor tissue was detected by using real-time polymerase chain reaction(PCR) with specific sequence,meanwhile the anti-tumor immune response was assayed by flow cytometric analysis and enzyme-linked immunosorbent spot(ELISPOT) assay.The results showed the toxicity and invasiveness of attenuated LM were decreased as compared with LM,and attenuated LM expressing MIA,especially the double-genes attenuated LM recombinant,could significantly induce anti-tumor immune response and inhibit tumor growth.This study implicates attenuated LM may be a safer and more effective vector for immunotherapy of melanoma.     

Are Infertile Men Less Healthy than Fertile Men? Results of a Prospective Case-Control Survey

Background

An association between either subfertility or infertility and an elevated risk of certain male cancers has been previously reported. Nothing is known about abnormalities in infertility and general health conditions.

Objective

To assess whether men with male factor infertility (MFI) are overall less healthy than fertile men, regardless of the reasons for infertility.

Design, setting, and participants

From September 2006 to September 2007, 344 consecutive European Caucasian men with MFI were enrolled in this prospective case-controlled study. Patients were compared with a control group of 293 consecutive age-comparable fertile men. Infertile men were consecutively attending the outpatient male reproductive clinic at a tertiary academic center. Fertile controls were consecutively recruited by use of advertisements posted within our hospital.

Measurements

Comorbidities of patients and fertile men were objectively scored with the Charlson Comorbidity Index (CCI) according to the International Classification of Diseases modified ninth version (ICD-9-CM) codes. Multivariate linear regression models tested the association between predictors and CCI score, as a proxy of general health status.

Results

According to the CCI scores, infertile men had a significantly higher rate of comorbidities compared with the fertile controls (CCI: 0.33 [0.8] vs 0.14 [0.5]; p < 0.001; 95% CI: 0.08–0.29). Linear regression analyses showed that although educational status did not have an impact on CCI (β: 0.035; p = 0.365), while CCI linearly increased with age (β: 0.196; p < 0.001) and body mass index (BMI; β: 0.161; p < 0.001). After adjusting for age, BMI, and educational status, a significantly lower CCI was calculated for fertile men and compared with MFI patients (β: −0.199; p < 0.001).

Conclusions

These results show that MFI accounts for a higher CCI, which may be considered a reliable proxy of a lower general health status.     

Obesity does not increase the risk of lymph node metastases in patients with clinically localized prostate cancer undergoing radical prostatectomy and extended pelvic lymph node dissection

Objectives: Several studies have shown that obesity is associated with more aggressive prostate cancer (PCa) variants. We hypothesized that obesity, quantified as body mass index (BMI), is associated with a higher risk of lymph node invasion (LNI) in patients undergoing extended pelvic lymph node dissection (ePLND). Methods: Clinical and pathological data were available for 994 consecutive men with PCa treated with radical prostatectomy (RP) and ePLND at a single European tertiary academic centre. Univariable and multivariable logistic regression analyses addressed the rate of LNI. Covariates consisted of pre‐treatment prostate specific antigen (PSA), biopsy Gleason sum, clinical stage history of diabetes mellitus as well as BMI coded as either continuous or categorized (<25, 25.0–29.9, 30 kg/m² or more) variable. Predictive accuracy was assessed with area under curve estimates. Results: Overall LNI was diagnosed in 105 patients (10.6%). Mean number of removed lymph nodes was 18.3 (range 7–60). Of all 994 patients, 372 (37.4%) were normal weight, 518 (52.1%) overweight, and 104 (10.5%) were clinically obese. Prevalence of LNI did not significantly differ across different BMI categories (<25, 25.0–29.9 and 30 kg/m² or more; 9.9, 10.6 and 12.5%, respectively; P = 0.75). In logistic regression models, neither continuously coded nor categorized BMI was a significant predictor of LNI at univariable or multivariable analyses (all P‐values ≥0.1). Moreover, inclusion of BMI with PSA, clinical stage, biopsy Gleason sum and presence of DM did not increase the ability of these variables to predict LNI (82.2% without BMI vs 82.5% and 82.9% with BMI coded as continuous and categorized variable, respectively; all P ≥ 0.4). Conclusions: In men undergoing RP and ePLND, increased BMI was not associated with increased risk of lymph node metastases. Therefore, routinely considering patient BMI in risk stratification schemes or prognostic LNI models may not be warranted.     

Mirizzi syndrome

Opinion statement Mirizzi syndrome is an important complication of gallstone disease. If not recognized preoperatively, it can result in significant morbidity and mortality. Preoperative diagnosis may be difficult despite the availability of multiple imaging modalities. Ul-trasonography (US), CT, and magnetic resonance cholangiopancreatography (MRCP) are common initial tests for suspected Mirizzi syndrome. Typical findings on US suggestive of Mirizzi syndrome are a shrunken gallbladder, impacted stone(s) in the cystic duct, a dilated intrahepatic tree, and common hepatic duct with a normal-sized common bile duct. The main role of CT is to differentiate Mirizzi syndrome from a malignancy in the area of porta hepatis or in the liver. MRI and MRCP are increasingly playing an important role and have the additional advantage of showing the extent of inflammation around the gallbladder that can help in the differentiation of Mirizzi syndrome from other gallbladder pathologies such as gallbladder malignancy. Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard in the diagnosis of Mirizzi syndrome. It delineates the cause, level, and extent of biliary obstruction, as well as ductal abnormalities, including fistula. ERCP also offers a variety of therapeutic options, such as stone extraction and biliary stent placement. Percutaneous cholangiogram can provide information similar to ERCP; however, ERCP has an additional advantage of identifying a low-lying cystic duct that may be missed on percutaneous cholangiogram. Wire-guided intraductal US can provide high-resolution images of the biliary tract and adjacent structures. Treatment is primarily surgical. Open surgery is the current standard for managing patients with Mirizzi syndrome. Good short-and long-term results with low mortality and morbidity have been reported with open surgical management. Laparoscopic management is contraindicated in many patients because of the increased risk of morbidity and mortality associated with this approach. Endoscopic treatment may serve as an alternative in patients who are poor surgical candidates, such as elderly patients or those with multiple comorbidities. Endoscopic treatment also can serve as a temporizing measure to provide biliary drainage in preparation for an elective surgery.     

Water permeability,hybrid layer long-term integrity and reaction mechanism of a two-step adhesive system

Objectives

Our aim was to investigate the reaction mechanism of formation of the hybrid layer by a HEMA-containing self-etch adhesive and to study fluid filtration, contact angle and interfacial ultrastructure by SEM following a 1 year ageing period.

Methods

Acidic behaviour and chemical interactions between Silorane System Adhesive and dentine were studied by potentiometric titrations, atomic absorption spectroscopy and infrared spectroscopy. The hydrophilicity of the adhesive was evaluated using the sessile drop method and dentine permeability by hydraulic conductance. The morphological study of the dentine/adhesive system interface was conducted using SEM.

Results

The Silorane System Adhesive behaved as a multi-acid with several different pK_a values. When the adhesive was in contact with dentine, the acid was progressively consumed and calcium ions were released. The acrylate substituted phosphonate bound strongly to apatite crystals. The polyacrylic acid copolymer reacted with calcium ions and formed an interpenetrating polymer network (IPN). Water contact angle measurements showed rapid spreading on primer (angles reached 15° at 30 s) and larger contact angles when the Silorane bonding layer was added (from over 60° to 44°). A thick, homogeneous hybrid layer was observed both initially and after 1 year of ageing, with a corresponding hydraulic conductance of −48.50% initially and −52.07% at 12 months.

Conclusion

The Silorane System Adhesive is capable of both dissolving calcium ions and binding to apatite surfaces. The results showed the hydrophilicity of the adhesive, which formed an IPN-like hybrid layer that conserved adequate impermeability over a 1-year period.