First molecular detection of porcine circovirus type 3 in dogs in China

Abstract

Porcine circovirus type 3 (PCV3) has recently been isolated from diseased pigs within the USA. The objective was to detect the presence of PCV3 in dogs. Nested polymerase chain reactions (PCR) with PCV3-specific primers for the capsid gene were used to detect PCV3 genomic DNA in serum samples from dogs (n = 44) in China. There was PCV3 DNA detected in 4 of 44 dogs [all were negative for PCV2 and canine circovirus (CanineCV)]. Based on sequence analysis, positive sequences were grouped into PCV3 genotypes. However, these isolates had close evolutionary relationships with FoxCV (KP941114) and CanineCV (JQ821392). Further investigations of the epidemiology, evolutionary biology, and pathobiology of PCV3 to dogs are warranted.

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Medicare For Dummies, 3rd Edition

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The Correlation of Allergic Rhinitis with ABO Phenotype

Abstract

The aim of study the correlation of ABO phenotypes in patients of allergic rhinitis and controls and to compare our study with the previous studies to analyse the association of above. 100 patients with symptoms of allergic rhinitis and 100 controls individual were selected from same geographical region and paired by gender and age were enrolled in the study. Detailed history, examination and relevant radiological and hematological investigations were done. ABO phenotypes were identified in red blood cells using hemagglutination technique. This clinic-based observational study was conducted among the patients presenting with signs and symptoms of allergic rhinitis. Maximum no. of cases were seen in ABO phenotype O (52%), followed by A, B and AB (33, 12 and 3% respectively) and it was found to be statistically significant (p = 0.001). Also more number of male patients were found in B and O blood group which was statistically significant (OR 5.33, p = 0.017 and OR 3.63, p = 0.006 respectively). Controls showed marginalized difference in distribution among the basis of different ABO phenotypes. The O blood group phenotype of ABO histo-blood group system is associated with AR. This study contributes to the better understanding of the pathophysiology and clinical variability of this disease and may help to improve strategies towards its prevention and diagnosis. Additionally, ABO histo-blood group phenotyping, an inexpensive and easy to perform assay could be used to identify individuals at risk of developing allergic rhinitis.

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Scrubbing your pearly whites with charcoal: Is it safe?

The competition ends with Nicole Scherzinger and Derek Hough taking home the mirror ball trophy on the 10th season of "Dancing with the Stars". From perky beauty bloggers on your Facebook feed to cold-pressed juice cleanses, activated charcoal seems to be the new super food.

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Initial results of a first-in-human study on the PlasmaWire™ System, a new radiofrequency wire for recanalization of chronic total occlusions

Abstract

Objectives

To examine the safety, efficacy, and efficiency of the PlasmaWire^TM System to recanalize coronary chronic total occlusions (CTO) using controlled ablation inside the CTO.

Background

The PlasmaWire^TM System is a new bipolar radiofrequency (RF) wire system utilizing plasma-mediated ablation to facilitate wire crossing in CTOs. Two independent PlasmaWire^TM wires are used in tandem for channel creation by applying RF energy between the tips so as to localize the ablation.

Methods

Prospective, nonrandomized, single-arm, multicenter study in seven patients with CTOs indicated for percutaneous coronary intervention (PCI).

Results

In this study, both wires were antegradely delivered to the distal end of CTO for antegrade re-entry in two cases and bidirectionally (antegrade and retrograde) delivered to the CTO for retrograde re-entry in five cases. In all cases, channel creation was achieved within a few seconds and was confirmed on angiogram or intravascular ultrasound (IVUS) and CTO recanalization was successfully achieved without any major adverse cardiac and cerebrovascular events (MACCE) or other minor complications. The clinical follow-up showed no clinical event at 1 month.

Conclusions

The PlasmaWire^TM System was shown to be safe and effective in obtaining CTO recanalization through a re-entry channel utilizing plasma-mediated ablation while reducing procedure time. The PlasmaWire™ System is a new bi-polar RF wire system utilizing plasma-mediated ablation for channel creation to facilitate CTO recanalization. This first-in-human study in which seven patients were enrolled was conducted to demonstrate the safety, efficacy, and efficiency of this system for CTO recanalization. Channels through the CTOs were successfully created within a few seconds by applying RF energy between the tips of two independent PlasmaWire^TM wires and recanalization was achieved in all cases without any complication. The PlasmaWire^TM System may safely facilitate CTO recanalization with less vessel injury and improve initial results of CTO PCI while reducing procedure time.

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Fractional flow reserve versus angiography guided percutaneous coronary intervention: An updated systematic review

Abstract

Objectives

To compare outcomes of fractional flow reserve (FFR) to angiography (ANGIO) guided percutaneous coronary intervention (PCI).

Background

The results of a recent randomized controlled trial reported unfavorable effects of routine measurement of FFR, thereby questioning its validity in improving clinical outcomes.

Methods

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were queried from January, 2000 through December, 2016 and studies comparing FFR and ANGIO guided PCI were included. Clinical endpoints assessed during hospitalization and at follow-up (>9 months) included: myocardial infarction (MI), major adverse cardiovascular events (MACE), target lesion revascularization (TLR), and all-cause mortality. Additional endpoints included number of PCIs performed, procedure cost, procedure time, contrast volume, and fluoroscopy time.

Results

A total of 51,350 patients (age 65 years, 73% male) were included from 11 studies. The use of FFR was associated with significantly lower likelihood of MI during hospitalization (OR 0.54, 95% CI: 0.39 to 0.75, P = 0.0003) and at follow-up (OR 0.53, 95% CI: 0.40 to 0.70, P = 0.00001). Similarly, FFR-PCI was associated with lower in-hospital MACE (OR 0.51, 95% CI: 0.37 to 0.70, P = 0.0001) and follow-up MACE (OR 0.63, 95% CI: 0.47 to 0.86, P = 0.004). In-hospital TLR was lower in the FFR-PCI group (OR 0.62, 95% CI: 0.40 to 0.97, P = 0.04), but not at follow-up (OR 0.83, 95% CI: 0.50 to 1.37, P = 0.46). There was no difference of in-hospital (OR 0.58, 95% CI: 0.31 to 1.09, P = 0.09) or follow-up all-cause mortality (OR 0.84, 95%CI: 0.59 to 1.20, P = 0.34). FFR-PCI was associated with significantly less PCI (OR 0.04, 95% CI: 0.01 to 0.15, P = 0.00001) with lower procedure cost (Mean Difference −4.27, 95% CI: −6.61 to −1.92, P = 0.0004). However, no difference in procedure time (Mean Difference 0.79, 95% CI: −2.41 to 3.99, P = 0.63), contrast use (Mean Difference −8.28, 95% CI: −24.25 to 7.68, P = 0.31) or fluoroscopy time (Mean Difference 0.38, 95% CI: −2.54 to 3.31, P = 0.80) was observed.

Conclusions

FFR-PCI as compared to ANGIO-PCI is associated with lower in-hospital and follow-up MI and MACE rates. Although, in-hospital TLR was lower in the FFR-PCI group, this benefit was not present after 9 months. FFR-PCI group was also associated with less PCI and lower procedure costs with no effect on procedure time, contrast volume or fluoroscopy time.

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Vascular complications after balloon aortic valvuloplasty in recent years: Incidence and comparison of two hemostatic devices

Abstract

Objectives

To define the incidence of vascular complications (VC) after balloon aortic valvuloplasty (BAV) in recent years, and to compare the performance of two vascular closure devices (VCD).

Background

VC remain the most frequent drawback of BAV and are associated with adverse clinical outcomes.

Methods

All BAV procedures performed at 2 high-volume centers over a 6-year period (n = 930) were collected in prospective registries and investigated to assess the incidence of Valve Academic Research Consortium-2 (VARC-2) defined VC. Incidence of life-threatening, major and minor bleeding was also assessed. In-hospital major adverse cardiac and cerebrovascular events (MACCE) rate (composite of in-hospital death, myocardial infarction, TIA/stroke, and life-threatening bleeding) as well as 30-day survival was compared between a suture-mediated closure system and a collagen plug hemostatic device.

Results

A 9 Fr arterial sheath was used in most of the patients (84.1%). Vascular closure was obtained with the Angio-Seal in 643 patients (69.1%) and the ProGlide in 287 (30.9%). The overall incidence of major VC was 2.7%, and minor VC 6.6%, without significant differences between groups. The Angio-Seal group was associated with a higher rate of small hematomas (6.9% vs. 3.5%, P = 0.042), whilst blood transfusions were more frequent in the ProGlide group (6.6% vs. 3.5%, P = 0.034). Rates of in-hospital MACCE and 30-day survival were similar. Use of either VCD was not independently associated with major VC.

Conclusions

VC rate after BAV is fairly low in experienced centers without major differences between the 2 most used VCD.

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Autovalidation and automation of the postanalytical phase of routine hematology and coagulation analyses in a university hospital laboratory

Authors: Mlinaric, Ana / Milos, Marija / Coen Herak, Désirée / Fucek, Mirjana / Rimac, Vladimira / Zadro, Renata / Rogic, Dunja


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Interlaboratory variability of urinary iodine measurements

Authors: Ittermann, Till / Johner, Simone / Below, Harald / Leiterer, Matthias / Thamm, Michael / Remer, Thomas / Völzke, Henry


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Hyperuricemia does not seem to be an independent risk factor for coronary heart disease

Authors: Battaggia, Alessandro / Scalisi, Andrea / Puccetti, Luca


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Development of an internally controlled quantitative PCR to measure total cell-associated HIV-1 DNA in blood

Authors: Vicenti, Ilaria / Meini, Genny / Saladini, Francesco / Giannini, Alessia / Boccuto, Adele / Schiaroli, Elisabetta / Zazzi, Maurizio


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Analytical quality: an unfinished journey

Authors: Plebani, Mario


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High-sensitivity assays for cardiac troponins – continued

Authors: Lackner, Karl J.


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Can a combination of average of normals and “real time” External Quality Assurance replace Internal Quality Control?

Authors: Badrick, Tony / Graham, Peter


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MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy

Authors: Yuan, Fang / Qiu, Zhao-Hui / Wang, Xing-Hua / Sun, Yu-Min / Wang, Jun / Li, Ruo-Gu / Liu, Hua / Zhang, Min / Shi, Hong-Yu / Zhao, Liang / Jiang, Wei-Feng / Liu, Xu / Qiu, Xing-Biao / Qu, Xin-Kai / Yang, Yi-Qing


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Stability of routine biochemical analytes in whole blood and plasma/serum: focus on potassium stability from lithium heparin

Authors: Dupuy, Anne Marie / Cristol, Jean Paul / Vincent, Bruno / Bargnoux, Anne Sophie / Mendes, Mickael / Philibert, Pascal / Klouche, Kadda / Badiou, Stéphanie


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The fentanyl family: A distinguished medical history tainted by abuse

Summary

What is known and objective

Beginning in the 1950s, a family of potent opioids was synthesized and developed (fentanyl and analogues). They continue to serve as valuable analgesic agents. But the recent spike and notoriety of their abuse has raised alarm, even calls for tighter control. We review the trajectory of these compounds.

Comment

To rectify shortcomings of the then available opioid analgesics, an analogue family of compounds was synthesized having a piperidine ring (presumptive principal active moiety in morphine and meperidine). The result was more potent and rapid-acting compounds, including alfentanil, carfentanil, fentanyl, sufentanil and others. These properties, plus availability in formulations for multiple routes of administration, impart broad therapeutic utility. They also unfortunately favour abuse.

What is new and conclusion

The abuse of fentanyl and its analogues (legal and illicit) serves as a case study for the dilemma and difficulties balancing a medical need against psychosocial realities. The fentanyl family provides relief for severe pain, but their very properties also engender abuse.

Chemical structures of morphine (left) and meperidine (right), highlighting the piperidine ring (dotted line).

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Assessing Doping Prevalence is Possible. So What Are We Waiting For?

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Low Energy Availability in Athletes: A Review of Prevalence, Dietary Patterns, Physiological Health, and Sports Performance

Abstract

In a high-performance sports environment, athletes can present with low energy availability (LEA) for a variety of reasons, ranging from not consuming enough food for their specific energy requirements to disordered eating behaviors. Both male and female high-performance athletes are at risk of LEA. Longstanding LEA can cause unfavorable physiological and psychological outcomes which have the potential to impair an athlete's health and sports performance. This narrative review summarizes the prevalence of LEA and its associations with athlete health and sports performance. It is evident in the published scientific literature that the methods used to determine LEA and its associated health outcomes vary. This contributes to poor recognition of the condition and its sequelae. This review also identifies interventions designed to improve health outcomes in athletes with LEA and indicates areas which warrant further investigation. While return-to-play guidelines have been developed for healthcare professionals to manage LEA in athletes, behavioral interventions to prevent the condition and manage its associated negative health and performance outcomes are required.

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Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update

Abstract

Survival rates for patients with medulloblastoma have improved in the last decades but for those who relapse outcome is dismal and new approaches are needed. Emerging drugs have been tested in the last two decades within the context of phase I/II trials. In parallel, advances in genetic profiling have permitted to identify key molecular alterations for which new strategies are being developed. We performed a systematic review focused on the design and outcome of early-phase trials evaluating new agents in patients with relapsed medulloblastoma. PubMed, clinicaltrials.gov, and references from selected studies were screened to identify phase I/II studies with reported results between 2000 and 2015 including patients with medulloblastoma aged <18 years. A total of 718 studies were reviewed and 78 satisfied eligibility criteria. Of those, 69% were phase I; 31% phase II. Half evaluated conventional chemotherapeutics and 35% targeted agents. Overall, 662 patients with medulloblastoma/primitive neuroectodermal tumors were included. The study designs and the response assessments were heterogeneous, limiting the comparisons among trials and the correct identification of active drugs. Median (range) objective response rate (ORR) for patients with medulloblastoma in phase I/II studies was 0% (0–100) and 6.5% (0–50), respectively. Temozolomide containing regimens had a median ORR of 16.5% (0–100). Smoothened inhibitors trials had a median ORR of 8% (3–8). Novel drugs have shown limited activity against relapsed medulloblastoma. Temozolomide might serve as backbone for new combinations. Novel and more homogenous trial designs might facilitate the development of new drugs.

This systematic review in early-phase trials in patients with medulloblastoma summarizes the recent experience in therapeutic strategies in patients with relapsed and refractory medulloblastoma and highlights the strengths and pitfalls of current trials.

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Racial disparities in pancreatic neuroendocrine tumors survival: a SEER study

Abstract

Pancreatic neuroendocrine tumor (pancreatic NETs), is an important cause of cancer-related death worldwide. No study has rigorously explored the impact of ethnicity on pancreatic NETs. We aimed to demonstrate the relationship between ethnicity and the survival of patients with pancreatic NETs. We used the SEER database to identify patients with pancreatic NETs from 2004 to 2013. Kaplan–Meier methods and Cox proportional hazard models were used to evaluate the impact of race on survival in pancreatic NETs patients. A total of 3850 patients were included: 3357 Non-Blacks, 493 Blacks. We stratified races as "Black" and "White/Other." Blacks were more likely to be diagnosed with later stages of tumors (P = 0.021). As for the treatment, the access to surgery seemed to be more limited in Blacks than non-Black patients (P = 0.012). Compared with non-Black patients, Black patients have worse overall survival (OS) (HR = 1.17, 95% CI: 1.00–1.37, P = 0.046) and pancreatic neuroendocrine tumors specific survival (PNSS) (HR = 1.22, 95% CI: 1.01–1.48, P = 0.044). Multivariate Cox analysis identified that disease extension at the time of diagnosis and surgical status contributed to the ethnical survival disparity. Black patients whose stages at diagnosis were localized had significantly worse OS (HR = 2.09, 95% CI: 1.18–3.71, P = 0.011) and PNSS (HR = 3.79, 95% CI: 1.62–8.82, P = 0.002). As for the patients who did not receive surgery, Blacks also have a worse OS (HR = 1.18, 95% CI: 1.00–1.41, P = 0.045). The Black patients had both worse OS and PNSS compared to non-Black patients. The restricted utilization of surgery, and the advanced disease extension at the time of diagnosis are the possible contributors to poorer survival of Blacks with pancreatic NETs.

Our work demonstrates that Blacks with pancreatic neuroendocrine tumors have poor survival than non-Black patients. The possible contributors to this survival disparity may be later diagnosis, less access to surgery and genetic differences.

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Incidence, risk factors, and outcomes of central venous catheter-related thromboembolism in breast cancer patients: the CAVECCAS study

Abstract

Previous epidemiologic studies investigating central venous catheter (CVC)-related venous thromboembolism (CRT) were conducted in heterogenous cancer populations and data in breast cancer (BC) remain limited. To investigate the Doppler ultrasound (DUS)-CRT incidence, risk factors and outcomes in BC, we designed a prospective, multicenter cohort of nonmetastatic invasive BC patients undergoing insertion of a CVC for chemotherapy. All patients underwent double-blind DUS before, 7, 30, and 90 days after CVC insertion and a 6 months clinical follow-up. Symptomatic DUS-CRT were treated by anticoagulants. D-Dimers, thrombin generation, and platelet-derived microparticles were measured before and 2 days after CVC placement. In DUS-CRT patients, a nested case–control study analyzed the role of thrombophilia. Among 524 patients, the DUS-CRT (14 symptomatic, 46 asymptomatic) cumulative probability was 9.6% at 3 months and 11.5% at 6 months (overall incidence rate: 2.18/100 patient-months). Ten/14 symptomatic DUS-CRT were detected on double-blind DUS before the clinical symptoms, and 3/14 had a simultaneous pulmonary embolism. No clinical thrombotic event subsequently occurred in untreated asymptomatic DUS-CRT. Age >50 years (OR, 1.80; 95% CI, 1.01–3.22), BMI >30 kg/m² (OR, 2.64; 95% CI, 1.46–4.76) and comorbidities (OR, 2.05; 95% CI, 1.18–3.56) were associated with DUS-CRT. No biomarkers was found to predict DUS-CRT. In multivariate analysis, BMI >30 kg/m² (OR, 2.66; 95%CI, 1.46–4.84) and lobular carcinoma histology (OR, 2.56; 95%CI, 1.32–4.96) remained the only significant DUS-CRT risk factors. Thrombophilia did not account for DUS-CRT. Only clinical parameters identified high risk DUS-CRT patients who may be considered for thromboprophylaxis.

Data regarding central venous catheter-related thrombosis (CRT) in breast cancer (BC) patients are limited, although CVC placement for chemotherapy is common in this population and BC is the first cause of cancer in women worldwide. We conducted a large prospective multicentre study (9 cancer hospitals, 524 patients). The 6-months cumulative probability of symptomatic and asymptomatic CRT was 11.5%. BMI >30 kg/m² and lobular carcinoma histology were the main risk factors for CRT.

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Social determinants of stage IV anal cancer and the impact of pelvic radiotherapy in the metastatic setting

Abstract

Anal cancer is a relatively rare malignancy, and a minority of patients present with metastatic disease in the United States. The National Cancer Database (NCDB) was used to identify factors associated with metastatic disease at presentation and evaluate the role of pelvic radiotherapy in these patients. The NCDB was queried for patients with squamous cell cancer of the anus diagnosed between 2004 and 2013. Patients were stratified by clinical stage at diagnosis, and a binary logistic regression model was created to identify factors associated with metastatic disease at diagnosis. A secondary metastatic cohort was generated and a multivariable Cox proportional hazards model was created to identify factors associated with improved survival. To validate findings, propensity-score matching was performed to generate a 1:1 paired dataset stratified by receipt of pelvic radiotherapy. The primary analysis cohort consisted of 28,500 patients. Facility location, male gender, and lack of insurance were confirmed as independent risk factors for metastatic disease. The metastatic cohort consisted of 1264 patients. Multivariable analysis confirmed female sex, possession of a private or Medicare insurance plan, pelvic radiotherapy, and chemotherapy as independent predictors of improved survival. A propensity-score matched cohort of 730 patients was generated. The median survival was 17.6 months in patients who received radiotherapy versus 14.5 months in those who did not (P < 0.01). In this cohort, male gender and lack of insurance were associated with metastatic disease at presentation. Furthermore, a significant benefit was associated with the use of pelvic radiotherapy. Future prospective research is warranted to confirm these findings.

Using the National Cancer Database, male gender, facility location, and lack of insurance were associated with metastatic disease at presentation. Furthermore, a significant benefit was associated with the use of pelvic radiotherapy in these patients.

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Modular training in cardiothoracic residency—practical considerations to revive and streamline Indian training systems

Abstract

Background

Modular training in cardiothoracic training is a structured approach to residency by standardising all the facets of resident training viz. knowledge, professionalism, communication and clinical skills, research and operative exposure needed for achieving a certain level of professional competence at the end of training.

Methods

Literature search was done using PubMed, Scopus and Google Scholar in view of writing a narrative review.

Results

The standardised approach can streamline the various national training programmes and promote effective mentorship. Imparting surgical skills to ensure technical proficiency in a structured manner assumes a central role in modular training which is a major departure from the current residency practises in our country.

Conclusion

Modular training model can improve the resident enrolment and quality of training in the long run.

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Custom Made Football Mouth Guards Getting Teens to Visit the Dentist

A football game might be the last place you expect to find an effort to get more teens to visit the dentist. But that's what's in the playbook of one Northeast Ohio dentist.

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Mobile phones and/or smartphones and their apps for teaching English as a foreign language

Abstract

Currently, there is an increasing trend in the shift from the use of traditional technologies such as a desktop computer towards the use of mobile technologies such as a mobile phone. Nearly all students nowadays own a mobile device and about half of them own more than one. Therefore, students are nowadays well equipped for mobile learning. The aim of this review is to explore the use of mobile phones and/or smartphones and their apps for teaching foreign languages, specifically English, and highlight their benefits and limitations for their use in the teaching of English as a foreign language. This was done by conducting a literature search in the databases Web of Science, Scopus, and ScienceDirect, and consequently, by evaluating the findings of the relevant studies. The findings indicate that the use of mobile phones and/or smartphones and their apps generate positive effects on learning English as a foreign language, especially in the development of learners' vocabulary and their increased motivation to study. Nevertheless, more longitudinal randomized controlled studies are needed to confirm the efficacy of the use of mobile phone and smartphone apps on specific language skills and knowledge.

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Application of learning analytics using clustering data Mining for Students’ disposition analysis

Abstract

Learning Analytics (LA) is an emerging field in which sophisticated analytic tools are used to improve learning and education. It draws from, and is closely tied to, a series of other fields of study like business intelligence, web analytics, academic analytics, educational data mining, and action analytics. The main objective of this research work is to find meaningful indicators or metrics in a learning context and to study the inter-relationships between these metrics using the concepts of Learning Analytics and Educational Data Mining, thereby, analyzing the effects of different features on student's performance using Disposition analysis. In this project, K-means clustering data mining technique is used to obtain clusters which are further mapped to find the important features of a learning context. Relationships between these features are identified to assess the student's performance.

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What Factors Influence Decision-Making about Breast Cancer Chemoprevention among High-Risk Women?

Estrogen exposure is one of the strongest risk factors for breast cancer development. Chemoprevention with selective estrogen receptor modulators (SERM), such as tamoxifen and raloxifene, has been shown in randomized controlled trials to reduce breast cancer incidence by up to 50% among high-risk women. Despite the strength of this evidence, there is significant underutilization of chemoprevention. Given the relatively few modifiable breast cancer risk factors, SERM use provides an important strategy for the primary prevention of this disease. Understanding factors which influence chemoprevention decision-making will inform efforts to implement breast cancer risk assessment and increase chemoprevention uptake in clinical practice. Cancer Prev Res; 10(11); 1–3. ©2017 AACR.

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NRG Oncology/National Surgical Adjuvant Breast and Bowel Project Decision-Making Project-1 Results: Decision Making in Breast Cancer Risk Reduction

Selective estrogen receptor modulators (SERMs) reduce breast cancer risk. Adoption of SERMs as prevention medication remains low. This is the first study to quantify social, cultural, and psychologic factors driving decision making regarding SERM use in women counseled on breast cancer prevention options. A survey study was conducted with women counseled by a health care provider (HCP) about SERMs. A statistical comparison of responses was performed between those who decided to use and those who decided not to use SERMs. Independent factors associated with the decision were determined using logistic regression. Of 1,023 participants, 726 made a decision: 324 (44.6%) decided to take a SERM and 402 (55.4%) decided not to. The most important factor for deciding on SERM use was the HCP recommendation. Other characteristics associated with the decision included attitudes and perceptions regarding medication intake, breast cancer worry, trust in HCP, family members with blood clots, and others' experiences with SERMs. The odds of SERM intake when HCP recommended were higher for participants with a positive attitude toward taking medications than for those with a negative attitude (P_interaction = 0.01). This study highlights the importance of social and cultural aspects for SERM decision making, most importantly personal beliefs and experiences. HCPs' recommendations play a statistically significant role in decision making and are more likely to be followed if in line with patients' attitudes. Results indicate the need for developing interventions for HCPs that not only focus on the presentation of medical information but, equally as important, on addressing patients' beliefs and experiences. Cancer Prev Res; 1–10. ©2017 AACR.

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Frequent immunoglobulin G4 expression in a common variant of primary cutaneous marginal zone B-cell lymphoma

Abstract

Immunoglobulin (Ig)G4 expression was recently observed in a proportion of primary cutaneous marginal zone B-cell lymphoma (PCMZL) with plasmacytic differentiation. IgG4-related disease is characterised by polyclonal lymphoplasmacytic infiltration with IgG4 expression, storiform fibrosis and obliterative phlebitis in histopathology. Here we report three cases of common variants of PCMZL with predominant and varied IgG4 expression, suggesting there is an underlying clonal progression between these two entities.

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Health and ecological risk assessment of heavy metals pollution in an antimony mining region: a case study from South China

Abstract

In recent years, international research on the toxicity of the heavy metal, antimony, has gradually changed focus from early medical and pharmacological toxicology to environmental toxicology and ecotoxicology. However, little research has been conducted for sources identification and risk management of heavy metals pollution by long-term antimony mining activities. In this study, a large number of investigations were conducted on the temporal and spatial distribution of antimony and related heavy metal contaminants (lead, zinc, and arsenic), as well as on the exposure risks for the population for the Yuxi river basin in the Hunan province, China. The scope of the investigations included mine water, waste rock, tailings, agricultural soil, surface water, river sediments, and groundwater sources of drinking water. Health and ecological risks from exposure to heavy metal pollution were evaluated. The main pollution sources of heavy metals in the Yuxi River basin were analyzed. Remediation programs and risk management strategies for heavy metal pollution were consequently proposed. This article provides a scientific basis for the risk assessment and management of heavy metal pollution caused by antimony basin ore mining.

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Growth promoting potential of fresh and stored Moringa oleifera leaf extracts in improving seedling vigor, growth and productivity of wheat crop

Abstract

Wheat is staple food of region, as it contributes 60% of daily caloric intake, but its delayed sowing reduces yield due to short life span. Moringa leaf extract (MLE) is considered to improve growth and development of field crops. Study comprised of two experiments. First experiment, freshly extracted MLE and in combination with growth-promoting substances were stored at two temperature regimes. Chemical analysis, after 1, 2, and 3 months' storage period, showed that phenolics and ascorbic acid concentrations decreased with increasing storage period. Fresh extracts improved speed and spread of emergence and seedling vigor. Effectiveness of MLE in terms of phenolics and ascorbate concentrations was highest up to 1 month which decreased with prolonged storage. Growth enhancing potential of MLE also reduced with increasing storage duration. Under field conditions, the bio-efficacy of these fresh and stored MLE was compared when applied as foliar spray at tillering and booting stages of wheat. Foliar applied fresh MLE was the most effective in improving growth parameters. Fresh MLE enhanced biochemical and yield attributes in late sown wheat. This growth-promoting potential of MLE decreased with storage time. Application of fresh MLE helped to achieve higher economic yield.

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Seasonal variation of heavy metals in water and sediments in the Halda River, Chittagong, Bangladesh

Abstract

The present study was carried out to assess the contamination levels of heavy metals (Pb, Cd, Cr, Cu, Hg, Al, Ni, Co, Zn, Mn) in surface water and sediment of the Halda River. The observed order of heavy metal concentration in water for Al > Ni > Zn > Mn > Cu > Cd > Pb > Cr > Co > Hg (mg/l) and for sediments Al > Mn > Zn > Ni > Cr > Pb > Cu > Co > Cd > Hg (mg/kg), respectively. The concentrations of Pb, Cd, Cr, Cu, Hg, Al, Ni, Co, Zn, and Mn in water, whereas in sediment Pb, Cu, Al, Ni, Co, Zn, and Mn were found above the permissible limit (WHO 2004; USEPA 2006; EPA 1986, 2002 and ECR 1997). Significant variations in the concentrations of Al and Ni were found in water (p < 0.05) while Cr, Cu, Pb, Co, Mn, and Ni showed substantial changes in sediment (p < 0.05). Principal component analysis (PCA) and correlation matrix revealed anthropogenic intrusions of Pb, Cd, Cr, Cu, Hg, Al, Ni, Co, Zn, and Mn in water and sediment. In case of water, very strong linear relationship was found in Hg vs Pb (0.941), Mn vs Zn (0.939), and Ni vs Cu (0.922) at the significance level 0.01. In sediment, very strong linear relationships were found in Mn vs Cr (0.999), Co vs Ni (0.999), Ni vs Cu (0.994), Zn vs Pb (0.993), Co vs Cu (0.992), Cu vs Cr (0.990), Mn vs Cu (0.989), Mn vs Ni (0.975), Mn vs Co (0.975), Ni vs Cr (0.974), Co vs Cr (0.972), Mn vs Pb (0.951), Cr vs Pb (0.948), Zn vs Cr (0.944), and Mn vs Zn (0.941) at the significance level 0.01 which direct that their common origin entirely from industrial effluents, municipal wastes, and agricultural activities. The study shows that seasonal water flows/water discharge (pre-monsoon, monsoon, and post-monsoon) have an impact on the mobility of metals. Elevated levels of metals were detected during monsoon in sediments (Pb, Cr, Cu, Al, Ni, Co, Zn, Mn) and post-monsoon in water (Cd, Hg, Ni, Co, Mn). The detection of high-risk metals in the Halda River may demonstrate that metals can cause significant effects on fry and fingerlings of the Gangetic carp fishery and prawn fishery (via sub-lethal and lethal effects and bioaccumulation or secondary poisoning of metals to fish and prawn).

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Calcineurin-mediated dephosphorylation of acetyl-coA carboxylase is required for PBAN-induced sex pheromone biosynthesis in Helicoverpa armigera [Research]

Chemical signaling plays a critical role in the behavior and physiology of many animals. Female insects, as a number of many other animals, release sex pheromones to attract males for mating. The evolutionary and ecological success of insects therefore hinges on their ability to precisely mediate (including initiation and termination) pheromone biosynthesis. Pheromone biosynthesis activating neuropeptide (PBAN) acts directly on pheromone glands to regulate sex pheromone production using Ca²⁺ and cyclic-AMP as secondary messengers in the majority of species. However, the molecular mechanism down-stream of the secondary messengers has not yet been elucidated in heliothine species. The present study shows that calcineurin, protein kinase A (PKA) and acetyl-coA carboxylase (ACC) are key components involved in PBAN-induced sex pheromone biosynthesis in Helicoverpa armigera using PBAN-dependent phosphoproteomics in combination with transcriptomics. RNAi-mediated knockdown and inhibitor assay demonstrated that calcineurin A is required for PBAN-induced ACC activation and sex pheromone production. Calcineurin-dependent phosphoproteomics and in vitro calcineurin phosphorylation assay further revealed that calcineurin regulated ACC activity by dephosphorylating ser84 and ser92. In addition, PKA-dependent phosphoproteomics and activity analysis revealed that PKA reduces the activity of AMP-activated protein kinase (AMPK), a negative regulator of ACC by phosphorylating the conserved ser92. Taken together, our findings indicate that calcineurin acts as the down-stream signal of PBAN/G-protein receptor/Ca²⁺ to activate ACC through dephosphorylation whilst inactivating AMPK via PKA to reduce ACC phosphorylation, thus facilitating calcineurin activation of ACC.

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Reconstitution of the core of the malaria parasite glideosome with recombinant Plasmodium class XIV myosin A and Plasmodium actin [Protein Structure and Folding]

Motility of the apicomplexan malaria parasite Plasmodium falciparum is enabled by a multi-protein glideosome complex, whose core is the class XIV myosin motor, PfMyoA and a divergent Plasmodium actin (PfACT1). Parasite motility is necessary for host cell invasion and virulence, but studying its molecular basis has been hampered by unavailability of sufficient amounts of PfMyoA. Here, we expressed milligram quantities of functional full-length PfMyoA with the baculovirus/Sf9 cell expression system, which required a UCS (UNC-45/CRO1/She4p) family myosin chaperone from Plasmodium spp. In addition to the known light chain MTIP, we identified an essential light chain (PfELC) that co-purified with PfMyoA isolated from parasite lysates. The speed at which PfMyoA moved actin was fastest with both light chains bound, consistent with the light chain-binding domain acting as a lever arm to amplify nucleotide-dependent motions in the motor domain. Surprisingly, PfELC binding to the heavy chain required that MTIP also be bound to the heavy chain, unlike MTIP that bound the heavy chain independently of PfELC. Neither the presence of calcium nor deletion of the MTIP N-terminal extension changed the speed of actin movement. Of note, PfMyoA moved filaments formed from Sf9 cell-expressed PfACT1 at the same speed as skeletal muscle actin. Duty ratio estimates suggested that as few as nine motors can power actin movement at maximal speed, a feature that may be necessitated by the dynamic nature of Plasmodium actin filaments in the parasite. In summary, we have reconstituted the essential core of the glideosome, enabling drug targeting of both of its core components to inhibit parasite invasion.

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Chicken galectin-1B inhibits Newcastle disease virus adsorption and replication through binding to HN glycoprotein [Molecular Bases of Disease]

Galectin-1 is an important immunoregulatory factor and can mediate the host-pathogen interaction via binding glycans on the surface of various viruses. We previously reported that avian respiratory viruses, including lentogenic Newcastle disease virus (NDV), can induce upregulation of chicken galectin (CG)-1B in the primary target organ. In this study, we investigated whether CG-1B participated in the infectious process of NDV in chickens. We demonstrated that velogenic NDV induced upregulation of CG-1B in target organs. We also found that CG-1B directly bound to NDV virions and inhibit their hemagglutination activity in vitro. We confirmed that CG-1B interacted with NDV hemagglutinin-neuraminidase (HN) glycoprotein, in which the specific G4 N-glycans significantly contributed to the interaction between CG-1B and HN glycoprotein. The presence of extracellular CG-1B, rather than the internalization process, inhibited adsorption of NDV. The interaction between intracellular CG-1B and NDV HN glycoprotein inhibited cell surface expression of HN glycoprotein and reduced the titer of progeny virus in NDV-infected DF-1 cells. Significantly, the replication of parental and HN glycosylation mutant viruses in CG-1B knockdown and overexpression cells demonstrated that the replication of NDV was correlated with the expression of CG-1B in a specific glycan-dependent manner. Collectively, our results indicate that CG-1B has anti-NDV activity by binding to N-glycans on HN glycoprotein.

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Structural analysis of the STAT1-STAT2 heterodimer revealed the mechanism of Sendai virus C protein-mediated blockade of type 1 interferon signaling [Protein Structure and Folding]

Sendai virus (SeV), which causes respiratory diseases in rodents, possesses the C protein that blocks the signal transduction of interferon (IFN), thereby escaping from host innate immunity. We previously demonstrated by using protein crystallography that two molecules of Y3 (C-terminal half of C protein) can bind to the homodimer of the N-terminal domain of STAT1 (STAT1ND), elucidating the mechanism of inhibition of IFN-γ signal transduction. SeV C protein also blocks the signal transduction of IFN-α/β by inhibiting the phosphorylation of STAT1 and STAT2, although the mechanism for the inhibition is unclear. Therefore, we sought to elucidate the mechanism of inhibition of IFN-signal transduction via STAT1 and STAT2. Small angle X-ray scattering (SAXS) analysis indicated that STAT1ND associates with the N-terminal domain of STAT2 (STAT2ND) with the help of a Gly-rich linker. We generated a linker-less recombinant protein possessing a STAT1ND:STAT2ND heterodimeric structure via an artificial disulfide bond. Analytical size-exclusion chromatography and surface plasmon resonance revealed that one molecule of Y3 can associate with a linker-less recombinant protein. We propose that one molecule of C protein associates with the STAT1:STAT2 heterodimer, inducing a conformational change to an antiparallel form, which is easily dephosphorylated. This suggests that association of C protein with the STAT1ND-STAT2ND heterodimer is an important factor to block the IFN-α/β signal transduction.

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Quantitative phosphoproteomics reveals involvement of multiple signaling pathways in early phagocytosis by the retinal pigmented epithelium [Protein Synthesis and Degradation]

One of the major biological functions of the retinal pigmented epithelium (RPE) is the clearance of shed photoreceptor outer segments (POS) through a multistep process resembling phagocytosis. RPE phagocytosis helps maintain the viability of photoreceptors that otherwise could succumb to the high metabolic flux and photo-oxidative stress associated with visual processing. The regulatory mechanisms underlying phagocytosis in the RPE are not fully understood, although dysfunction of this process contributes to the pathogenesis of multiple human retinal degenerative disorders, including age-related macular degeneration. Here, we present an integrated transcriptomic, proteomic, and phosphoproteomic analysis of phagocytosing RPE cells, utilizing three different experimental models: human-derived RPE-like cell line, ARPE-19, cultured murine primary RPE cells, and RPE samples from live mice. Our combined results indicated that early stages of phagocytosis in the RPE are mainly characterized by pronounced changes in the protein phosphorylation level. Global phosphoprotein enrichment analysis revealed involvement of PI3K/Akt, mechanistic target of rapamycin (mTOR), and MEK/ERK pathways in the regulation of RPE phagocytosis, confirmed by immunoblot analyses and in vitro phagocytosis assays. Most strikingly, phagocytosis of POS by cultured RPE cells was almost completely blocked by pharmacological inhibition of phosphorylation of Akt. Our findings, along with those of previous studies, indicate that these phosphorylation events allow the RPE to integrate multiple signals instigated by shed POS at different stages of the phagocytic process.

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Lactate-mediated mitoribosomal defects impair mitochondrial oxidative phosphorylation and promote hepatoma cell invasiveness [Gene Regulation]

Impaired mitochondrial oxidative phosphorylation (OXPHOS) capacity, accompanied by enhanced glycolysis, is a key metabolic feature of cancer cells, but its underlying mechanism remains unclear. Previously, we reported that human hepatoma cells that harbor OXPHOS defects exhibit high tumor cell invasiveness via elevated claudin-1 (CLN1). In the present study, we show that OXPHOS-defective hepatoma cells (SNU354 and SNU423 cell lines) exhibit reduced expression of mitochondrial ribosomal protein L13 (MRPL13), a mitochondrial ribosome (mitoribosome) subunit, suggesting a ribosomal defect. Specific inhibition of mitoribosomal translation by doxycycline, chloramphenicol or siRNA-mediated MRPL13 knockdown decreased mitochondrial protein expression, reduced oxygen consumption rate (OCR), and increased CLN1-mediated tumor cell invasiveness in SNU387 cells, which have active mitochondria. Interestingly, we also found that exogenous lactate treatment suppressed MRPL13 expression and OCR and induced CLN1 expression. A bioinformatic analysis of the open RNA-Seq database from The Cancer Genome Atlas Liver Hepatocellular carcinoma (TCGA-LIHC) cohort revealed a significant negative correlation between MRPL13 and CLN1 expression. Moreover, in patients with low MRPL13 expression, two oxidative metabolic indicators, pyruvate dehydrogenase B expression and the ratio of lactate dehydrogenase (LDH) type B to LDH type A, significantly and negatively correlated with CLN1 expression, indicating that the combination of elevated glycolysis and deficient MRPL13 activity was closely linked to CLN1-mediated tumor activity in LIHC. These results suggest that OXPHOS defects may be initiated and propagated by lactate-mediated mitoribosomal deficiencies and that these deficiencies are critically involved in LIHC development.

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Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe.Design Retrospective cohort study.Setting Publicly accessible...

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Music Perception Training for Pediatric Cochlear Implant Recipients Ages 3 to 5 Years: A Pilot Study

Abstract

This study examined the potential effectiveness of music perception training program for pediatric cochlear implant recipients. A pilot study was conducted with six young CI recipients with a mean age of 4.4 years to investigate the applicability of the systematic training program targeting discrimination and identification of rhythm, pitch, and timbre, and singing skills. Participants received a total of 24 training sessions and their music perception task performance on seven subtests was measured before and after the program. The results showed that task performance rates of participants increased for all subtests, with significant improvement in rhythm discrimination and identification. This indicates that this structured training could be applied to this population in order to facilitate them to effectively process temporal and spectral features of music.

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Exploring the Meaning of a Performance in Music Therapy for Children and Their Families Experiencing Homelessness and Family Violence

Abstract

This qualitative project explored the experience and meaning of a supported group performance held at the conclusion of a music therapy program for children and their families who were receiving support for homelessness and family violence. Interviews were conducted with three preadolescent girls who had participated in the group performance, as well as four parents who were audience members. An interpretative phenomenological analysis explored some of the similarities and differences experienced by participants. The performance was a multifaceted experience, with both positive and challenging aspects described. Three recurrent themes were identified: the children experienced intense, but mixed, emotions; the performance connected the children to their family and peers; and the audience played an active role in the performance. The findings emphasize the ways performance provides opportunities for families to positively engage with one another, and support each other, during times of crisis.

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Evaluating a Pilot Improvisational Drumming Curriculum: Implications for Improving Confidence and Skills among Music Therapy Students

Abstract

Presented here are performance results of music therapy students in a college course that was designed to prepare them to use percussion interventions in therapy. After discussing the purpose and teaching methods used, self-reported confidence levels were examined to determine the effects of training in the use of common drum circle instruments and experience facilitating drum circles in a small-group setting. Data consisted of results from surveys regarding confidence and perceived skills. Mean confidence scores data were analyzed through graphical presentation. Mean self-reported skill-level scores were also compared to the mean scores given by the instructor for each question on the skills survey. Examination of the data indicated a positive trend for self-reported confidence and drumming-skill levels. Comparison of instructor scores and student scores indicated strong agreement between teacher and student assessment of skills. In addition, skill-level trends supported the idea that student confidence increased as skill level increased.

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Case Study: The Feasibility of Using Song to Cue Expressive Language in Children with Specific Language Impairment

Abstract

In this feasibility trial, song cues were compared to traditional speech cues in the acquisition of syntax and morphology for two preschool children with Specific Language Impairment. Acceptability, practicality, and intensity of treatment were considered. Fewer sessions were required in the song modality to achieve syntax goals, but neither participant achieved a morphology goal. Indications were that melodic and rhythmic features associated with song may be more efficient for syntax learning than inflectional morphology learning. Findings from the trial provide promising evidence and direction for larger trials of the intervention.

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Characterizing Objective Observations in Music Therapy: A Study of Student Practicum Logs

Abstract

Students can have difficulty learning to make and document objective observations of music therapy sessions. With the intention of supporting undergraduate students to learn this skill, 130 student practicum logs were qualitatively analyzed to identify concepts involved in the process of doing so. Results revealed when it is important to observe in music therapy sessions, who and what it is important to observe, and how to describe observations. Application of the results to student learning has the potential to increase the efficacy and efficiency of this teaching/learning process.

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Surgical Music Therapy: The Significance and Implementation of Music Therapy in the Operating Arena

Abstract

While music therapy is rarely practiced perioperatively, an extensive body of research confirms the efficacy of music therapy with comparable medical populations. Numerous music-in-medicine and music therapy studies suggest that surgical music therapy (SMT) may in fact be beneficial in the perioperative realm. In this article, SMT experiences are relayed, offering goals, suggestions, and challenges in its facilitation. Methods, practices, and professional issues related to expediting music therapy in the surgical arena are discussed, with the objective of inspiring real-world applications and further research in this area. In so doing, this article articulates the potential of SMT to serve as an adjunct to standard surgical care and illustrates how music therapists might introduce and expand SMT practices at hospitals and surgery centers nationwide.

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Perception of Community and Learning in a Distance and Resident Graduate Course

Abstract

Distance-learning opportunities have increased drastically in higher education over the past decade; however, there is little research on music therapy student perceptions of distance and online education. The purpose of this study was to measure perception of community (POC), perception of learning (POL), and academic performance in students enrolled in a graduate course offered face-to-face to resident-instruction (RI) students and online to distance-learning (DL) students. Participants for this study included 28 distance students and 14 resident students. Ratings on the survey indicated that students enrolled in both sections of the course had a high POL and moderate POC. An independent samples t-test indicated a significant between-group difference in POL for RI and DL students, with higher mean scores in DL students. There were no significant between-group differences for POC or academic scores. Linear regression indicated that years of experience was a significant predictor of POL. Results of this study indicated that both RI and DL students enrolled in sections of the same course had similar POC. Students in the DL section of the course showed significantly higher POL, which may be attributed to the DL student class being composed of professional students returning to school to gain further education after working in the field.

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Musical Mnemonics Training: Proposed Mechanisms and Case Example with Acquired Brain Injury

Abstract

After an acquired brain injury, simple semantic, declarative memory tasks such as knowing one's address can be difficult to complete. Music's ability to extend and optimize shared neurologic pathways responsible for music perception, production, and memory processes makes rhythmic-melodic templates uniquely suited for declarative memorization tasks. Rhythm and melody have long been used to memorize information, and many have direct experience learning the letters of their alphabet using the familiar childhood song "Twinkle Twinkle." Therapeutic applications for musical mnemonics exist in both child and adult populations. Typically developing children, children with special needs, and those who have sustained neurologic injury or disease processes affecting memory may benefit from training using musical mnemonics. The purposes of this paper are to provide an overview of memory processing, review the research literature on music-mediated memory tasks in clinical populations experiencing impairments in memory, and describe suggested mechanisms for their action using the Rational-Scientific Mediating Model (Thaut, 2005). An intervention example utilizing the Transformational Design Model (TDM) will demonstrate how this technique can be implemented in a clinical setting.

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The power of music: Pioneering discoveries in the new science of song The music instinct: Science & song

Mannes, E. (2011). The Power of Music: Pioneering Discoveries in the New Science of Song. New York: Walker & Company. 263 pages. ISBN: 978-0-8027-1996-6. $11.95/$19.60.

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Music therapy in schools: Working with children of all ages in mainstream and special education

Tomlinson, Jo, Derrington, Philippa, and Oldfield, Amelia (Eds.). (2012). Music therapy in schools: Working with children of all ages in mainstream and special education. Jessica Kingsley Publishers. 227 pages. $39.95. ISBN 987-1-84905-000-5, ebook ISBN 9780857004741.

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I Will Follow You: The Combined Use of Songwriting and Art to Promote Healing in a Child Who Has Been Traumatized

Abstract

This article describes music therapy services provided to a six-year-old child who had been physically and sexually abused. While the music therapist had been meeting with the child for over a year at the time of this writing, this report focuses on an intervention implemented over the course of approximately six months. It presents a new way of combining songwriting and visual art to facilitate emotional expression, specifically, the use of therapist-composed songs in response to the child's drawings. The drawings and therapist-composed songs are related to emotions that the child chose as being important for her healing. Several processes are explained, including (a) how the child was encouraged to use visual art, (b) how the therapist composed each song, and (c) how the child responded to the therapist-composed songs. The paper further summarizes the essential elements of this approach, including giving the child control of the process, providing validation and acceptance for the child and where she is in the healing process, increasing her self-esteem, and providing a healthy emotional outlet. Three audio examples are included with their corresponding drawings. The clinical considerations of establishing sufficient rapport with the child, already having a strong songwriting background, flexibility with the various ways a song can be written and the client's chosen level of involvement, and collaborating with an art therapist are included in the discussion of this paper.

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Adolescents’ Evaluation of Music Therapy in an Inpatient Psychiatric Unit: A Quality Improvement Project

Abstract

Consistent with Quality Improvement initiatives in health care and at Grand River Hospital, a quality assessment of the music therapy program at the Child & Adolescent Mental Health unit was conducted. Medical Students administered the surveys in which youth were asked to rate their experiences with music in general on a 4-point scale, and specifically with this music therapy program on a 5-point scale. Youth were also asked to provide their perceptions of aspects of the music therapy they considered helpful, challenging or needed attention. This report is based on the 72 youth who participated in music therapy and completed an anonymous evaluation survey. The mean age of participants was 14.88 (SD 1.77), 48 (67%) identified as female, and most 57/66 or 86% reported some type of anxiety. Youth indicated that the music therapy was helpful for elevating their mood, reducing anxiety and in socially interacting with others. Suggestions for quality improvement are offered.

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Countertransference in End-of-Life Music Therapy

Abstract

Countertransference is a complex and important issue for end-of-life music therapists. However, limited literature is available on the subject of end-of-life music therapy and countertransference to guide professionals as we encounter the effects of countertransference inside and outside sessions. There are circumstances associated with end-of-life music therapy that require a closer look, that demand recognition, and that may result in better music experiences for our clients. The purpose of this article is to explore the experiences and influences of countertransference in the unique situations presented by end-of-life music therapy, thus increasing readers' awareness of the potential impact of countertransference upon their clinical practices.

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Industrial Lead Poisoning in Los Angeles: Anatomy of a Public Health Failure

Environmental Justice , Vol. 0, No. 0.


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Public Drinking Water System Coverage and Its Discontents: The Prevalence and Severity of Water Access Problems in California's Mobile Home Parks

Environmental Justice , Vol. 0, No. 0.


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Administrative Persistence in the Face of a Hostile Regime: How the Environmental Protection Agency Can Survive the Trump Administration

Environmental Justice , Vol. 0, No. 0.


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Shipping Fracking Wastes on the Ohio River: A Case Study in Effective Public Advocacy and How Citizen Groups Can Do Even Better

Environmental Justice , Vol. 0, No. 0.


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Full-length mutation search of the TP53 gene in acute myeloid leukemia has increased significance as a prognostic factor

Abstract

TP53 gene abnormality has been reported to be an unfavorable prognostic factor in acute myeloid leukemia (AML). However, almost all studies of TP53 gene abnormality so far have been limited to mutation searches in the DNA binding domain. As there have been few reports examining both mutation and deletion over the full-length of the TP53 gene, the clinical characteristics of TP53 gene abnormality have not yet been clearly established. In this study, TP53 gene mutation was observed in 7.3% of the total 412 de novo AML cases (33 mutations in 30 cases), with mutation outside the DNA binding domain in eight cases (27%). TP53 gene deletion was observed in 3.1% of 358 cases. All cases had monoallelic deletion with TP53 gene mutation on the opposite allele. Multivariate analysis demonstrated that TP53 gene mutation in the DNA binding domain and outside the DNA binding domain was an independent poor prognostic factor for overall survival and relapse-free survival among the total cohort and it is also an unfavorable prognostic factor in FLT3-ITD-negative AML cases aged 70 years or below with intermediate cytogenetic prognosis. In stratified treatment, full-length search for TP53 gene mutation is therefore very important.

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Metabolic characteristics of programmed cell death-ligand 1-expressing lung cancer on 18F-fluorodeoxyglucose positron emission tomography/computed tomography

Abstract

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have been identified as novel targets of immunotherapy of lung cancer. In present study, we evaluated the metabolic characteristics of lung cancer by using ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) with regard to PD-L1 protein expression. PD-L1 protein expression was evaluated by immunohistochemistry with the antibody clone SP142 in 579 surgically resected primary lung cancer patients. Cases with less than 5% tumor membrane staining were considered negative. We examined the association between the frequency of PD-L1 protein expression and the maximum standardized uptake value (SUVmax) in preoperative ¹⁸F-FDG PET/CT. The cut-off values for SUVmax were determined by receiver operating characteristic curve analyses. The SUVmax was significantly higher in nonsmall cell lung cancer (NSCLC) patients with PD-L1 protein expression compared with those without PD-L1 protein expression (P < 0.0001). However, there was no correlation between SUVmax and PD-L1 protein expression in patients with neuroendocrine tumors (P = 0.6545). Multivariate analysis revealed that smoking, the presence of pleural invasion, and high SUVmax were independent predictors of PD-L1 positivity. PD-L1-expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative ¹⁸F-FDG PET/CT was a predictor of PD-L1 protein expression in patients with NSCLC.

PD-L1-expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative 18F-FDG PET/CT was a predictor of PD-L1 protein expression in patients with NSCLC.

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EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represent a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft (PDX) model that is intrinsically resistant to the RTKI sunitinib but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its anti-angiogenic and anti-metastatic activity but lost its direct anti-tumor effects due to kinome reprogramming, which resulted in suppression of pro-apoptotic and cell cycle regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTK, restoring the anti-tumor effects of sunitnib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.

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Novel selective agents for the degradation of androgen receptor variants to treat castration-resistant prostate cancer

Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of next-generation therapeutics to manage advanced PCa.

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Bisphosphonate-functionalized coordination polymer nanoparticles for the treatment of bone metastatic breast cancer

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): Yuanfeng He, Yanjuan Huang, Ziyuan Huang, Yali Jiang, Xiaoqi Sun, Yifeng Shen, Weijing Chu, Chunshun Zhao
Bone is the most common organ affected by metastatic breast cancer. Targeting cancers within the bone remains a great challenge due to the inefficient delivery of therapeutic to bone. In this study, a polyethylene glycol (PEG) coated nanoparticles (NPs) made of a Zn²⁺ coordination polymer was linked with a bone seeking moiety, alendronate (ALN), to deliver cisplatin prodrug (DSP) to the bone. The particle sizes of this novel system, DSP-Zn@PEG-ALN NPs, were regulated by adjusting the volume ratio of water phase to oil phase in microemulsion. It was small enough (about 55nm) to extravasate through the clefts (80nm) of the bone's sinusoidal capillaries and localize into metastatic bones. DSP-Zn@PEG-ALN NPs showed much higher affinity for hydroxyapatite in vitro and bone in vivo than non-targeted DSP-Zn@PEG NPs and cisplatin. In addition, the in vivo biodistribution studies demonstrated that about 4-fold of platinum was delivered to the bone metastatic lesions than that in healthy bones by DSP-Zn@PEG-ALN NPs intravenously. Finally, DSP-Zn@PEG-ALN NPs not only inhibited the tumor growth efficiently but also reduced the osteocalastic bone destruction. Besides, DSP-Zn@PEG-ALN NPs showed significantly reduced toxicity of cisplatin. These results indicate that the DSP-Zn@PEG-ALN NPs have a great potential in enhancing chemotherapeutic efficacy for the treatment of bone metastatic breast cancer.

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Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): Guillem Pascual-Pasto, Nagore G. Olaciregui, Javier A.W. Opezzo, Helena Castillo-Ecija, Maria Cuadrado-Vilanova, Sonia Paco, Ezequiel M. Rivero, Monica Vila-Ubach, Camilo A. Restrepo-Perdomo, Montserrat Torrebadell, Mariona Suñol, Paula Schaiquevich, Jaume Mora, Guillermo F. Bramuglia, Guillermo L. Chantada, Angel M. Carcaboso
Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P=0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P=0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma.Chemical compounds included in this manuscriptTopotecan (PubChem CID: 60700)Pantoprazole sodium (PubChem CID: 15008962)

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Effective treatment of drug resistant recurrent breast tumors harboring cancer stem-like cells by staurosporine/epirubicin co-loaded polymeric micelles

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): Juanjuan Zhang, Hiroaki Kinoh, Louise Hespel, Xueying Liu, Sabina Quader, John Martin, Tsukasa Chida, Horacio Cabral, Kazunori Kataoka
Breast cancer recurrence and resistance are associated with cancer stem-like cell (CSC) sub-populations. As conventional therapies fail to treat CSCs, institution of novel therapeutic strategies capable of eradicating both cancer cells and CSCs is central for achieving effective treatments with long-term survival. Here, we studied the ability of polymeric micelles cooperatively loading the cytotoxic drug epirubicin (Epi) and the CSC inhibitor staurosporine (STS) to treat breast tumors, particularly when tumors relapsed after chemotherapy. The STS/Epi-loaded micelles (STS/Epi/m) demonstrated potent therapeutic efficacy against both naïve orthotopic 4T1-luc breast tumors and their recurrent Epi-resistant counterparts, significantly prolonging survival. This efficacy enhancement of STS/Epi/m was correlated with the ability of the micelles to suppress the CSC-associated sub-populations of breast cancer, i.e. the aldehyde dehydrogenase-positive (ALDH⁺) population and the CD44⁺/CD24⁻ fraction, in Epi-resistant cells and tumors. These results demonstrated STS/Epi/m as a promising strategy for effective management of breast cancer.

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Oral delivery of Escherichia coli persistently infected with M2e-displaying bacteriophages partially protects against influenza A virus

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): Lei Deng, Kenny Roose, Emma R. Job, Riet De Rycke, Evelien Van Hamme, Amanda Gonçalves, Eef Parthoens, Laetitia Cicchelero, Niek Sanders, Walter Fiers, Xavier Saelens
We describe a novel live oral vaccine type. Conceptually, this vaccine is based on a non-lytic, recombinant filamentous bacteriophage that displays an antigen of interest. To provide proof of concept we used the amino-terminal part of a conserved influenza A virus epitope, i.e. matrix protein 2 ectodomain (M2e) residues 2 to 16, as the antigen of interest. Rather than using the phages as purified virus-like particles as a vaccine, these phages were delivered to intestinal Peyer's patches as a live bacterium-phage combination that comprises Escherichia coli cells that conditionally express invasin derived from Yersinia pseudotuberculosis. Invasin-expressing E. coli cells were internalized by mammalian Hep-2 cells in vitro and adhered to mouse intestinal microfold (M) cells ex vivo. Invasin-expressing E. coli cells were permissive for recombinant filamentous bacteriophage f88 that displays M2e and became persistently infected. Oral administration of the live engineered E. coli-invasin-phage combination to mice induced M2e-specific serum IgG antibodies. Mice that had been immunized with invasin-expressing E. coli cells that carried M2e2-16 displaying fd phages seroconverted to M2e and showed partial protection against challenge with influenza A virus. Oral delivery of a live vaccine comprising a bacterial host that is targeted to Peyer's patches and is persistently infected with an antigen-displaying phage, can thus be exploited as an oral vaccine.

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A facile approach to functionalizing cell membrane-coated nanoparticles with neurotoxin-derived peptide for brain-targeted drug delivery

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): Zhilan Chai, Xuefeng Hu, Xiaoli Wei, Changyou Zhan, Linwei Lu, Kuan Jiang, Bingxia Su, Huitong Ruan, Danni Ran, Ronnie H. Fang, Liangfang Zhang, Weiyue Lu
The blood brain barrier separates the circulating blood from the extracellular fluid in the central nervous system and thus presents an essential obstacle to brain transport of therapeutics. Herein, we report on an effective brain-targeted drug delivery system that combines a robust red blood cell membrane-coated nanoparticle (RBCNP) with a unique neurotoxin-derived targeting moiety. The RBCNPs retain the complex biological functions of natural cell membranes while exhibiting physicochemical properties that are suitable for effective drug delivery. CDX peptide is derived from candoxin and shows high binding affinity with nicotinic acetylcholine receptors (nAChRs) expressed on the surface of brain endothelial cells. Through a facile yet robust approach, we successfully incorporate ^DCDX peptides onto the surface of RBCNPs without compromising the peptide's brain targeting ability. The resulting ^DCDX-RBCNPs show promising brain targeting efficiency both in vitro and in vivo. Using a glioma mouse model, we demonstrate that doxorubicin-loaded ^DCDX-RBCNPs have superior therapeutic efficacy and markedly reduced toxicity as compared to the nontargeted drug formulations. While RBCNPs are used as a model system to evaluate the surface modification approach, the reported method can be readily generalized to various types of cell membrane-derived nanocarriers for broad medical applications.

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Nano-delivery system targeting to cancer stem cell cluster of differentiation biomarkers

Publication date: 28 November 2017
Source:Journal of Controlled Release, Volume 266
Author(s): Ahad Mokhtarzadeh, Soodabeh Hassanpour, Zahra Farajzadeh Vahid, Maryam Hejazi, Maryam Hashemi, Javad Ranjbari, Maryam Tabarzad, Saeed Noorolyai, Miguel de la Guardia
Cancer stem cells (CSCs) are one of the most important origins of cancer progression and metastasis. CSCs have unique self-renewal properties and diverse cell membrane receptors that induced the resistance to the conventional chemotherapeutic agents. Therefore, the therapeutic removal of CSCs could result in the cancer cure with lack of recurrence and metastasis. In this regard, targeting CSCs in accordance to their specific biomarkers is a talented attitude in cancer therapy. Various CSCs surface biomarkers have been described, which some of them exhibited similarities on different cancer cell types, while the others are cancer specific and have just been reported on one or a few types of cancers. In this review, the importance of CSCs in cancer development and therapeutic response has been stated. Different CSCs cluster of differentiation (CD) biomarkers and their specific function and applications in the treatment of cancers have been discussed, Special attention has been made on targeted nano-delivery systems. In this regard, several examples have been illustrated concerning specific natural and artificial ligands against CSCs CD biomarkers that could be decorated on various nanoparticulated drug delivery systems to enhance therapeutic index of chemotherapeutic agents or anticancer gene therapy. The outlook of CSCs biomarkers discovery and therapeutic/diagnostic applications was discussed.

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ImmunoPET imaging of tissue factor expression in pancreatic cancer with 89Zr-Df-ALT-836

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): Reinier Hernandez, Christopher G. England, Yunan Yang, Hector F. Valdovinos, Bai Liu, Hing C. Wong, Todd E. Barnhart, Weibo Cai
Overexpression of tissue factor (TF) has been associated with increased tumor growth, tumor angiogenesis, and metastatic potential in many malignancies, including pancreatic cancer. Additionally, high TF expression was shown to strongly correlate with poor prognoses and decreased survival in pancreatic cancer patients. Herein, we exploited the potential targeting of TF for positron emission tomography (PET) imaging of pancreatic cancer. The TF-targeted tracer was developed through radiolabeling of the anti-human TF monoclonal antibody (ALT-836) with ⁸⁹Zr. The tracer was characterized by fluorescence microscopy and flow cytometry assays in BXPC-3 and PANC-1 cells, two pancreatic cancer cell lines with high and low TF expression levels, respectively. Non-invasive PET scans were acquired in tumor-bearing mice injected with ⁸⁹Zr-Df-ALT-836. Additionally, ex vivo biodistribution, blocking, and histological studies were performed to establish the affinity and specificity of ⁸⁹Zr-Df-ALT-836 for TF in vivo. ⁸⁹Zr-labeling of Df-ALT-836 was achieved in high yield and good specific activity. Flow cytometry and microscopy studies revealed no detectable difference in TF-binding affinity between ALT-836 and Df-ALT-836 in vitro. Longitudinal PET scans unveiled a lasting and prominent ⁸⁹Zr-Df-ALT-836 uptake in BXPC-3 tumors (peak at 31.5±6.0%ID/g at 48h post-injection; n=3), which was significantly abrogated (2.3±0.5%ID/g at 48h post-injection; n=3) when mice were pre-injected with a blocking dose (50mg/kg) of unlabeled ALT-836. Ex vivo biodistribution data confirmed the accuracy of the PET results, and histological analysis correlated high tumor uptake with in situ TF expression. Taken together, these results attest to the excellent affinity and TF-specificity of ⁸⁹Zr-Df-ALT-836. With elevated, persistent, and specific accumulation in TF-positive BXPC-3 tumors, PET imaging using ⁸⁹Zr-Df-ALT-836 promises to open new avenues for improving future diagnosis, stratification, and treatment response assessment in pancreatic cancer patients.

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Graphical Abstracts Contents Listing

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264





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Injectable nanomedicine hydrogel for local chemotherapy of glioblastoma after surgical resection

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): C. Bastiancich, J. Bianco, K. Vanvarenberg, B. Ucakar, N. Joudiou, B. Gallez, G. Bastiat, F. Lagarce, V. Préat, F. Danhier
Glioblastoma (GBM) treatment includes, when possible, surgical resection of the tumor followed by radiotherapy and oral chemotherapy with temozolomide, however recurrences quickly develop around the resection cavity borders leading to patient death. We hypothesize that the local delivery of Lauroyl-gemcitabine lipid nanocapsule based hydrogel (GemC12-LNC) in the tumor resection cavity of GBM is a promising strategy as it would allow to bypass the blood brain barrier, thus reaching high local concentrations of the drug. The cytotoxicity and internalization pathways of GemC12-LNC were studied on different GBM cell lines (U251, T98-G, 9L-LacZ, U-87 MG). The GemC12-LNC hydrogel was well tolerated when injected in mouse brain. In an orthotopic xenograft model, after intratumoral administration, GemC12-LNC significantly increased mice survival compared to the controls. Moreover, its ability to delay tumor recurrences was demonstrated after perisurgical administration in the GBM resection cavity. In conclusion, we demonstrate that GemC12-LNC hydrogel could be considered as a promising tool for the post-resection management of GBM, prior to the standard of care chemo-radiation.

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Tumor-homing, pH- and ultrasound-responsive polypeptide-doxorubicin nanoconjugates overcome doxorubicin resistance in cancer therapy

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): Zhuoran Wang, Qiong He, Wenguo Zhao, Jianwen Luo, Weiping Gao
Nanomedicines hold promise in overcoming drug resistance in cancer therapy, but the in vivo therapeutic efficacy is limited by their inefficient tumor targeting, poor tumor penetration, low cellular uptake and insufficient drug release. Here we report tumor-homing, pH- and ultrasound-responsive polypeptide-doxorubicin nanoconjugates for overcoming doxorubicin resistance. These nanoconjugates show accelerated cellular uptake and doxorubicin release and thus enhanced cytotoxicity to doxorubicin-resistant cancer cells when exposed to ultrasound. In a doxorubicin-resistant breast cancer mouse model, they exhibited improved tumor accumulation and penetration following exposure to ultrasound. More importantly, they displayed significantly improved in vivo anticancer efficacy without appreciable side effects post ultrasound irradiation. These findings suggest that these nanoconjugates are promising as a new class of intelligent nanomedicines for overcoming drug resistance in cancer therapy.

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Co-delivery of autoantigen and dexamethasone in incomplete Freund's adjuvant ameliorates experimental autoimmune encephalomyelitis

Publication date: 28 November 2017
Source:Journal of Controlled Release, Volume 266
Author(s): Laura Northrup, J. Daniel Griffin, Matthew A. Christopher, Lorena R. Antunez, Brittany L. Hartwell, Chad J. Pickens, Cory Berkland
Current therapies for autoimmune diseases focus on treating the symptoms rather than the underlying disease cause. A major setback in improving current therapeutics for autoimmunity is the lack of antigen specificity. Successful antigen-specific immunotherapy (ASIT) would allow for improved treatment of autoimmune diseases. In this work, dexamethasone was co-delivered with autoantigen (PLP) in vivo to create effective ASIT for the treatment of experimental autoimmune encephalomyelitis (EAE). Using an emulsion of incomplete Freund's adjuvant (IFA) as a co-delivery vehicle, it was discovered that the controlled release of autoantigen was important for the suppression of clinical disease symptoms. Analysis of the immune response via cytokines revealed that dexamethasone was important for shifting the immune response away from inflammation. Co-delivery of both autoantigen and dexamethasone increased B-cell populations and antibody production, signifying an increased humoral immune response. Overall, this data indicated that the co-delivery of PLP and dexamethasone with a water-in-oil emulsion is effective in treating a murine autoimmune model.

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Protease-activatable cell-penetrating peptide possessing ROS-triggered phase transition for enhanced cancer therapy

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): Jisang Yoo, N. Sanoj Rejinold, DaeYong Lee, Sangyong Jon, Yeu-Chun Kim
Reactive oxygen species (ROS)- or protease-responsive materials have been utilized as carriers in cancer therapies because ROS and specific proteases are overproduced in cancer cells. Methionine-based polypeptides containing a thioether group are promising candidates due to their ROS-responsiveness which provides a phase transition. Herein, we developed protease-activatable cell-penetrating peptide containing a ROS-responsive methionine, a cell permeable lysine chain, and a matrix metalloproteinase (MMP)-cleavable linker. We designed a poly(l-methionine-block-l-lysine)-PLGLAG-PEG (MLMP) and doxorubicin (DOX) was loaded into the micelle core. The MLMP exhibited MMP-sensitive cleavage and ROS-induced DOX release. Moreover, we confirmed efficient DOX delivery into cancer cells and induction of the apoptotic capability in vitro. In a bio-distribution study, IR-780 dye encapsulated MLMP showed superior tumor targetability with long retention. Furthermore, MLMP (DOX) exhibited outstanding tumor inhibition capability with non-toxicity compared to free DOX, indicating that dual stimuli-MLMP has great potential as an anticancer drug delivery platform.

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Tolerance of high and low amounts of PLGA microspheres loaded with mineralocorticoid receptor antagonist in retinal target site

Publication date: 28 November 2017
Source:Journal of Controlled Release, Volume 266
Author(s): Min Zhao, Esther Rodríguez-Villagra, Laura Kowalczuk, Manon Le Normand, Marianne Berdugo, Rinath Levy-Boukris, Ikram El Zaoui, Béatrice Kaufmann, Robert Gurny, Irene Bravo-Osuna, Irene T. Molina-Martínez, Rocío Herrero-Vanrell, Francine Behar-Cohen
Mineralocorticoid receptor (MR) contributes to retinal/choroidal homeostasis. Excess MR activation has been shown to be involved in pathogenesis of central serous chorioretinopathy (CSCR). Systemic administration of MR antagonist (MRA) reduces subretinal fluid and choroidal vasodilation, and improves the visual acuity in CSCR patients. To achieve long term beneficial effects in the eye while avoiding systemic side-effects, we propose the use of biodegradable spironolactone-loaded poly-lactic-co-glycolic acid (PLGA) microspheres (MSs). In this work we have evaluated the ocular tolerance of MSs containing spironolactone in rat' eyes. As previous step, we have also studied the tolerance of the commercial solution of canrenoate salt, active metabolite of spironolactone. PLGA MSs allowed in vitro sustained release of spironolactone for 30days. Rat eyes injected with high intravitreous concentration of PLGA MSs (10mg/mL) unloaded and loaded with spironolactone maintained intact retinal lamination at 1month. However enhanced glial fibrillary acidic protein immunostaining and activated microglia/macrophages witness retinal stress were observed. ERG also showed impaired photoreceptor function. Intravitreous PLGA MSs concentration of 2mg/mL unloaded and loaded with spironolactone resulted well tolerated. We observed reduced microglial/macrophage activation in rat retina compared to high concentration of MSs with normal retinal function according to ERG. Spironolactone released from low concentration of MSs was active in the rat retina. Low concentration of spironolactone-loaded PLGA MSs could be a safe therapeutic choice for chorioretinal disorders in which illicit MR activation could be pathogenic.

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Extracellular vesicles from mesenchymal stem cells activates VEGF receptors and accelerates recovery of hindlimb ischemia

Publication date: 28 October 2017
Source:Journal of Controlled Release, Volume 264
Author(s): Prakash Gangadaran, Ramya Lakshmi Rajendran, Ho Won Lee, Senthilkumar Kalimuthu, Chae Moon Hong, Shin Young Jeong, Sang-Woo Lee, Jaetae Lee, Byeong-Cheol Ahn
Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are potential therapies for various diseases, but their angiogenic mechanisms of therapeutic efficacy remain unclear. Here, we describe how MSC-EVs, activates VEGF receptors and downstream angiogenesis pathways. Mouse MSC-EVs were isolated from cell culture medium and characterized using transmission electron microscopy, nanoparticle analysis, and western blotting. In vitro migration, proliferation, and tube formation assays using endothelial cells were used to assess the angiogenic potential of MSC-EVs, and revealed higher levels of cellular migration, proliferation, and tube formation after treatment. qRT-PCR and western blotting (WB) revealed higher protein and mRNA expression of the angiogenic genes VEGFR1 and VEGFR2 in mouse SVEC-4 endothelial cells after MSC-EVs treatment. Additionally, other vital pro-angiogenic pathways (SRC, AKT, and ERK) were activated by in vitro MSC-EV treatment. WB and qRT-PCR revealed enriched presence of VEGF protein and miR-210-3p in MSC-EV. The hindlimb ischemia mouse model was established and MSC-EVs with or without Matrigel (EV-MSC+Gel) were injected into the ischemic area and blood reperfusion was monitored using molecular imaging techniques. The in vivo administration of MSC-EVs increased both blood reperfusion and the formation of new blood vessels in the ischemic limb, with the addition of matrigel enhancing this effect further by releasing EVs slowly. MSC-EVs enhance angiogenesis in ischemic limbs, most likely via the overexpression of VEGFR1 and VEGFR2 in endothelial cells. These findings reveal a novel mechanism of activating receptors by MSC-EVs influence the angiogenesis.

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