Detection of specific chromosomal aberrations in urine using BCA-1 (oligo-CGH-array) enhances diagnostic sensitivity and predicts the aggressiveness of non-muscle-invasive bladder transitional cell carcinoma

Introduction

Bladder carcinoma (B-TCC) is the fifth most prevalent carcinoma in the United States (US) or Europe. In addition, B-TCC is the most expensive carcinoma per patient between diagnosis and death, because of its 50–80 % recurrence rate. B-TCC is an optimal carcinoma for which to detect DNA alterations in urine, which is easily obtainable. Chromosomal aberrations in tumors have been closely related to the carcinogenesis process.

Material and Methods

We developed a highly specific and sensitive oligo-CGH-array for the diagnosis and follow-up of B-TCC, based on the detection of chromosomal aberrations in urine samples. One hundred and sixty-four urine samples were analyzed. The qualitative results, including chromosomal aberrations, were obtained. Quantitative results are expressed as a percentage of chromosomal alterations on the autosomes.

Results

From the urine samples, we were able to differentiate B-TCC from non-malignant conditions with an accuracy of 100 % for patients without history of B-TCC. For follow-up of B-TCC in clinical practice, at least a deletion (8p; 9p; 9q) or a cut-off of >2 % of chromosomal imbalance was considered as a positive test. According to our criteria, 100 % of high-grade tumors were diagnosed, and the sensitivity to predict positive cystoscopy was 95 % (specificity 73 %). A cut-off >9 % was a strong signature of high-grade TCC (odds ratio 53 CI 95 % 7–417; p = 0.0002).

Conclusion

We developed a sensitive clinical tool for the detection of B-TCC using DNA extracted from patient urine. This tool is also able to identify low-grade B-TCC and identify high-risk patients harboring a high-grade disease.     

Development of EGFR-Targeted Nanoemulsion for Imaging and Novel Platinum Therapy of Ovarian Cancer

Purpose

Platinum-based chemotherapy is the treatment of choice for malignant epithelial ovarian cancers, but generalized toxicity and platinum resistance limits its use. Theranostic nanoemulsion with a novel platinum prodrug, myrisplatin, and the pro-apoptotic agent, C₆-ceramide, were designed to overcome these limitations.

Methods

The nanoemulsions, including ones with an EGFR binding peptide and gadolinium, were made using generally regarded as safe grade excipients and a high shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3, A2780 and A2780_CP.

Results

The nanoemulsion with particle size <150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and EGFR-targeted nanoemulsions; improved cytotoxicity was observed for the these nanoemulsions with the latter showing a 50-fold drop in the IC₅₀ in SKOV3 cells as compared to cisplatin alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist^®.

Conclusion

The myrisplatin/C₆-ceramide nanoemulsion synergistically enhanced in vitro cytotoxicity. An EGFR binding peptide addition further increased in vitro cytotoxicity in EGFR positive cancer cells. The diagnostic version showed MR imaging similar to the clinically relevant Magnevist® and may be suitable as a theranostic for ovarian cancer.     

Biodistribution and Pharmacokinetics of Dapivirine-Loaded Nanoparticles after Vaginal Delivery in Mice

Purpose

To assess the potential of polymeric nanoparticles (NPs) to affect the genital distribution and local and systemic pharmacokinetics (PK) of the anti-HIV microbicide drug candidate dapivirine after vaginal delivery.

Methods

Dapivirine-loaded, poly(ethylene oxide)-coated poly(epsilon-caprolactone) (PEO-PCL) NPs were prepared by a nanoprecipitation method. Genital distribution of NPs and their ability to modify the PK of dapivirine up to 24 h was assessed after vaginal instillation in a female mouse model. Also, the safety of NPs upon daily administration for 14 days was assessed by histological analysis and chemokine/cytokine content in vaginal lavages.

Results

PEO-PCL NPs (180–200 nm) were rapidly eliminated after administration but able to distribute throughout the vagina and lower uterus, and capable of tackling mucus and penetrate the epithelial lining. Nanocarriers modified the PK of dapivirine, with higher drug levels being recovered from vaginal lavages and vaginal/lower uterine tissues as compared to a drug suspension. Systemic drug exposure was reduced when NPs were used. Also, NPs were shown safe upon administration for 14 days.

Conclusions

Dapivirine-loaded PEO-PCL NPs were able to provide likely favorable genital drug levels, thus attesting the potential value of using this vaginal drug delivery nanosystem in the context of HIV prophylaxis.     

Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide

In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes in both the “established CV disease” (CVD) and “CV risk factor” subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD from those used in REWIND. The present post hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re-categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P-interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum.     

Chinese Journal of Traumatology won the financial aid from ＂Global Influ- ence Promotion Project for Chinese Scientific and Technical Journals＂

Objective： To determine the frequency of adrenal injuries in patients presenting with blunt abdomi- nal trauma by computed tomography （CT）. Methods： During a 6 month period from January 1, 2011 to June 30, 2011, 82 emergency CT examinations were performed in the setting of major abdominal trauma and ret- rospectively reviewed for adrenal gland injuries. Results： A total of 7 patients were identified as having adrenal gland injuries （6 males and 1 female）. Two patients had isolated adrenal gland injuries. In the other 5 patients with nonisolated injuries, injuries to the liver （1 case）, spleen （1 case）, retroperitoneum （2 cases） and mesentery （4 cases） were identified. Overall 24 cases with liver injuries （29 %）, 11cases with splenic injuries （13%）, 54 cases with mesenteric injuries （65%）, 14 cases （17%） with retroperitoneal injuries and 9 cases with renal injuries were identified. Conclusion： Adrenal gland injury is identified in 7 patients （11.7%） out of a total of 82 patients who underwent CT after major abdominal trauma. Most of these cases were nonisolated injuries. Our experience indicates that adrenal injury resulting from trauma is more common than suggested by other reports. The rise in incidence of adrenal injuries could be attributed to the mode of injury.     

Chemometric Models for Quantification of Carbamazepine Anhydrous and Dihydrate Forms in the Formulation

Carbamazepine (CBZ) exists in anhydrous and dihydrate forms. These forms differ in their solubility, dissolution rate, and subsequently in their oral bioavailability. The objective of this study is to develop multivariate chemometric models for estimation of the low level of carbamazepine dihydrate (CBZ-DH) in the CBZ formulations containing excipients of the commercial formulation. The selected excipients were mixed in proportions to make sample matrices ranging from 0% to 50% CBZ-DH. Fourier transform infrared (FTIR), near infrared (NIR), and hyperspectral imaging data were mathematically pretreated before the development of partial least square and principal component analysis regression models. The developed partial least squares regression and principal component analysis models demonstrated predictability of CBZ and CBZ-DH by multiple scattering correction and standard normal variate processing methods. Among the spectroscopic techniques used the model performance parameters such as root-mean-square error, standard error, and bias were found to be low for NIR compared to FTIR. The treated data have shown better model fitting than without treatment, which was demonstrated by correlation coefficient of 0.9778, 0.9824, and 0.9852 for FTIR, NIR, and hyperspectral imaging, respectively. Furthermore, the predicted values were found to be very close to the selected low level of independent samples having 5% CBZ-DH in tablet formulation.     

Estimation of Cardiac Depressant Activity of Ten Medicinal Plant Extracts from Pakistan

Ten medicinal plants extracts were pharmacologically screened for their cardiac activity on isolated rabbit heart, and showed significant negative inotropic activity with negative chronotropic effects. In all cases alcohol dried extracts were used and reconstituted in either water or ethyl acetate for these tests. The plant extracts which produced cardiac depression were Cactus grandiflora , Carissa carandas Linn., Duranta repens Linn., Eclipta prostrata Roxb., Heliotropium ophioglossum , Prosopis glandulosa , Scheweinfurthia sphaerocarpa A. Br., Solanum surattense Burm. f., Tephrosia uniflora Pers., Nardostachys jatamansi Dc. (Syn. Valeriana jatamansi ).     

Review of policies,data, and interventions to improve maternal nutrition in Afghanistan

Malnutrition contributes to direct and indirect causes of maternal mortality, which is particularly high in Afghanistan. Women's nutritional status before, during, and after pregnancy affects their own well‐being and mortality risk and their children's health outcomes. Though maternal nutrition interventions have documented positive impact on select child health outcomes, there are limited data regarding the effects of maternal nutrition interventions on maternal health outcomes globally. This scoping review maps policies, data, and interventions aiming to address poor maternal nutrition outcomes in Afghanistan. We used broad search categories and approaches including database and website searches, hand searches of reference lists from relevant articles, policy and programme document requests, and key informant interviews. Inclusion and exclusion criteria were developed by type of source document, such as studies with measures related to maternal nutrition, relevant policies and strategies, and programmatic research or evaluation by a third party with explicit interventions targeting maternal nutrition. We abstracted documents systematically, summarized content, and synthesized data. We included 20 policies and strategies, 29 data reports, and nine intervention evaluations. The availability of maternal nutrition intervention data and the inclusion of nutrition indicators, such as minimum dietary diversity, have increased substantially since 2013, yet few nutrition evaluations and population surveys include maternal outcomes as primary or even secondary outcomes. There is little evidence on the effectiveness of interventions that target maternal nutrition in Afghanistan. Policies and strategies more recently have shifted towards multisectoral efforts and specifically target nutrition needs of adolescent girls and women of reproductive age. This scoping review presents evidence from more than 10 years of efforts to improve the maternal nutrition status of Afghan women. We recommend a combination of investments in measuring maternal nutrition indicators and improving maternal nutrition knowledge and behaviours.