Mesenchymal stem cells for treating ocular surface diseases

Mesenchymal stem cells (MSC) have become a promising tool for cell therapy in regenerative medicine. They are readily available, demonstrate powerful differentiation capabilities and present immunosuppressive properties that aid them in surviving from host immune rejection for its great potential use in allograft. Currently clinical trials are underway using MSC, both culture-expanded allogeneic and autologous, for the treatment of a range of diseases not treatable by conventional therapies. A vast array of studies has dedicated towards the use of MSC for treating corneal diseases with very promising outcomes. MSC have successfully differentiated into keratocytes both in vitro and in vivo, and corneal epithelial cells in vitro, but it is uncertain if MSC can assume corneal epithelial cells in vivo. However, to date few studies have unequivocally established the efficacy of MSC for treating corneal endothelial defects. Currently, the diversity in protocols of the isolation and expansion of MSC are hindering to the assessment of cell treatment ability and the further development of treatment regimens. Therefore, future studies should develop international standards for MSC isolation and characterization. In this review, we discuss recent advances in MSC for treating ocular surface diseases.     

Macrolides increase the expression of 11β‐hydroxysteroid dehydrogenase 1 in human sinonasal epithelium,contributing to glucocorticoid activation in sinonasal mucosa

Background and Purpose

The anti‐inflammatory and immunomodulatory effects of macrolides include the ability to decrease mucus secretion and inhibit inflammatory mediators in chronic rhinosinusitis. Nevertheless, their mechanisms of action remain to be determined. Here we have investigated the effects of macrolide antibiotics (clarithromycin, azithromycin and josamycin; representating the 14‐, 15‐ and 16‐membered macrolides) on endogenous steroids in human sinonasal epithelial cells and mouse nasal mucosa.

Experimental Approach

The effects of macrolides on the expression of steroid‐converting enzymes [11β‐hydroxysteroid dehydrogenase (11β‐HSD1 and 11β‐HSD2)], steroid‐synthesizing enzymes (3β‐HSD, CYP21, CYP11B1 and CYP11A1) and cortisol levels were assessed in cultured human epithelial cells. In control and adrenalectomized mice , these enzymes and corticosterone levels were evaluated in nasal mucosa and serum after administration of macrolides.

Key Results

The expression levels of 3β‐HSD, CYP21, 11β‐HSD1 and CYP11B1 increased in human epithelial cells treated with clarithromycin and azithromycin, whereas the expression levels of 11β‐HSD2 and CYP11A1 were not affected. Josamycin had no effects on the expression of these enzymes. Cortisol levels increased in epithelial cells treated with clarithromycin or azithromycin. The expression of 3β‐HSD, CYP11A1, CYP21, CYP11B1 and 11β‐HSD1 was upregulated in nasal mucosa of mice treated with clarithromycin or azithromycin, but not in adrenalectomized mice.

Conclusions and Implications

This study provides evidence that 14‐ and 15‐membered macrolide antibiotics may affect the expression of steroid‐synthesizing and steroid‐converting enzymes in human sinonasal epithelial cells and mouse nasal mucosa, increasing the endogenous cortisol levels in sinonasal mucosa.

Abbreviations

11β‐HSD1

11β‐hydroxysteroid dehydrogenase 1

11β‐HSD2

11β‐hydroxysteroid dehydrogenase 2

3β‐HSD

3β‐hydroxysteroid dehydrogenase

CYP21A1

cytochrome P450, family 21, subfamily A, polypeptide 1

CYP11B1

cytochrome P450, family 11, subfamily B, polypeptide 1

CYP11A1

cytochrome P450, family 11, subfamily A, polypeptide 1

CRS

chronic rhinosinusitis

PBS‐T

phosphate‐buffered saline‐Tween 20

PF

915275, N‐(6‐amino‐2‐pyridinyl)‐4''‐cyano‐[1,1''‐biphenyl]‐4‐sulfonamide

siRNA

small interfering RNA

     

Two-stage designs in bioequivalence trials

Purpose

The aim of this study is to assess the current status of non-fixed sample size designs in bioequivalence trials with a focus on two-stage adaptive approaches.

Methods

We searched PubMed and Google Scholar from inception to October 2014. Regulatory guidelines were obtained from the public domain. Different methods were compared by Monte Carlo simulations for their impact on the patient’s and producer’s risks.

Results

Add-on designs, group sequential designs and adaptive two-stage sequential designs are currently accepted to demonstrate bioequivalence in various regulations. All three approaches may inflate the patient’s risk if applied inconsiderately. Direct transfer of methods developed for superiority testing to bioequivalence is not warranted. Published two-stage frameworks maintain the type I error and generally the desired power. Adaptation based on the observed T/R ratio observed in the first stage should be applied with caution. Monte Carlo simulations are an efficient tool to explore the operating characteristics of methods.

Conclusions

Validated two-stage frameworks can be applied without requiring the sponsor to perform own simulations—which could further improve power based on additional assumptions. Two-stage designs are both ethical and economical alternatives to fixed sample designs.

     

Increased brain uptake of venlafaxine loaded solid lipid nanoparticles by overcoming the efflux function and expression of P-gp

Venlafaxine (VLX) could be pumped out of the brain by P-glycoprotein (P-gp). Moreover, the expression of P-gp distributed in blood–brain barrier could be significantly induced by VLX. Thus, P-gp could be considered as the nature barrier for delivering of VLX to the brain. The aim of this study was to investigate whether the efflux function and increased expression of P-gp could be reversed by utilizing solid lipid nanoparticles (SLN). VLX solid lipid nanoparticles (VLX ? SLN) were prepared and evaluated. Pharmacokinetics and brain distribution of VLX in different formulations were conducted after oral or intravenous administration. P-gp efflux function to VLX was evaluated by the brain uptake amount of VLX, while P-gp expression was investigated by Western blotting. Results indicated that the entrapment, mean size and zata potential of VLX ? SLN was 74.9 ± 3.0 %, 186.3 ± 69.26 nm and ?22.8 ± 7.78 mv, respectively. After vein injection of VLX formulations, the brain uptake amount of VLX from VLX ? SLN was significantly higher than that of VLX solution, VLX solution with empty SLN (VLX+ empty SLN) and VLX solution with Verapamil (VLX + Ver), respectively. Furthermore, the protein mass of P-gp in VLX ? SLN treated group was the lowest among all the investigated groups. These results indicated that SLN could overcome P-gp and achieve brain target by intravenous administration.     

Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis

Adriamycin (doxorubicin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is limited by the development of a cumulative and irreversible cardiomyopathy. Although the drug affects numerous structures in different cell types, the mitochondrion appears to a principal subcellular target for the development of cardiomyopathy. This review describes evidence demonstrating that adriamycin redox cycles on complex I of the mitochondrial electron transport chain to liberate highly reactive free radical species of molecular oxygen. The primary effect of adriamycin on mitochondrial performance is the interference with oxidative phosphorylation and inhibition of ATP synthesis. Free radicals liberated from adriamycin redox cycling are thought to be responsible for many of the secondary effects of adriamycin, including lipid peroxidation, the oxidation of both proteins and DNA, and the depletion of glutathione and pyridine nucleotide reducing equivalents in the cell. It is this altered redox status that is believed to cause assorted changes in intracellular regulation, including the induction of the mitochondrial permeability transition and complete loss of mitochondrial integrity and function. Associated with this is the interference with mitochondrial-mediated cell calcium signaling, which is implicated as essential to the capacity of mitochondria to participate in bioenergetic regulation in response to external signals reflecting changes in metabolic demand. If taken to an extreme, this loss of mitochondrial plasticity may manifest in the liberation of signals mediating either oncotic or necrotic cell death, further perpetuating the cardiac failure associated with adriamycin-induced mitochondrial cardiomyopathy.     

Comparison of hydrocolonic sonograpy accuracy in preoperative staging between colon and rectal cancer

AIM: To compare the accuracy of hydrocolonic sonography (HUS) in determining the depth of invasion (T stage) in colon and rectal cancer. METHODS: A total of 1 000-2 000 mL of saline was instilled per rectum using a system for barium enemas, and then ultrasonography was conducted by a SSA-270A (Toshiba Co, Japan) sonolayer unit with a 3.75 MHz for 17 patients with colon cancer and 13 patients with rectal cancer before operation. After operation, T stage in HUS was compared with postoperative histological findings. RESULTS: Overall, the accuracy of T stage was 70%. It was 88% in colon cancer and 46% in rectal cancer. In evaluating nodal state, the accuracy of HUS was low in both colon (71%) and rectal cancers (46%) compared with conventional CT or MRI. The overall accuracy of N staging was 60%. CONCLUSION: HUS is valuable to evaluate the depth of invasion in colon cancer, but is less valuable in rectal cancer. Because HUS is low-cost, noninvasive, and readily available at any place, this technique seems to be useful to determine the preoperative staging in colon cancer, but not in rectal cancer.     

Iodine-125 seed brachytherapy for early stage prostate cancer: a single-institution review

Purpose

We are reporting the five-year biochemical control, toxicity profile and dosimetric parameters using iodine-125 low dose rate brachytherapy (BT) as monotherapy for early stage prostate cancer at a single institution.

Material and methods

Between April 2006 and December 2010, 169 men with early stage prostate cancer were treated with BT. Biochemical failure was defined using the Phoenix definition (nadir?+?2 ng/mL). Treatment-related morbidities, including urinary, rectal and sexual function, were measured, applying the International Prostate Symptom Score (IPSS), the 7-grade Quality of Life Scale (QoL) and medical status, the International Consultation on Incontinence Modular Questionnaire (ICIQ), the International Index of Erectile Function (IIEF-5) and the Common Terminology Criteria for Adverse Events (CTCAE v4.03). Seed migration and loss, dosimetric parameters and learning effects were also analyzed.

Results

Medium follow-up time was 50 months (range, 1–85 months). The five-year biochemical failure rate was 7%. Acute proctitis rates were 19% (grade 1) and 1% (grade 2), respectively. The overall incidence of incontinence was 19% (mild), 16% (moderate) and?<?1% (severe). An increase in IPSS?≥?5 points was detected in 59% of patients, with 38% regaining their baseline. Seed dislocation was found in 24% of patients and correlated with D90 and V100. A learning curve was found for seed migration, D90 and V100. QoL correlated with the general health condition of patient, incontinence symptoms and IPSS.

Conclusions

BT for early stage prostate cancer offers excellent five-year biochemical control with low toxicities. QoL aspects are favorable. A learning curve was detected for procedural aspects but its impact on patient relevant endpoints remains inconclusive.

     

The Basic Facts of Korean Breast Cancer in 2012: Results from a Nationwide Survey and Breast Cancer Registry Database

The Korean Breast Cancer Society has constructed a nationwide breast cancer database through utilization of an online registration program. We have reported the basic facts about breast cancer in Korea in 2012, and analyzed the changing patterns in the clinical characteristics and management of breast cancer in Korea over the last 10 years. Data on patients newly diagnosed with breast cancer were collected for the year 2012 from 97 hospitals and clinics nationwide using a questionnaire survey, and from the online registry database. A total of 17,792 patients were newly diagnosed with breast cancer in 2012. The crude incidence rate of female breast cancer, including invasive cancer and in situ cancer, was 70.7 cases per 100,000 women. The median age at diagnosis was 51 years, and the proportion of postmenopausal women was higher than that of premenopausal women among those diagnosed with breast cancer. The proportion of cases of early breast cancer increased continuously, and breast-conserving surgery was performed in more cases than total mastectomy in that same year. The total number of breast reconstruction surgeries increased approximately 3-fold over last 10 years. The 5-year overall survival rate for all stages of breast cancer patients was extremely high. The clinical characteristics of breast cancer have changed in ways that resulted in high overall survival over the past 10 years in Korea, and the surgical management of the disease has changed accordingly. Analysis of nationwide registry data will contribute to a better understanding of the characteristics of breast cancer in Korea.