Author: jackiewe

Hot Topics: Advances in Gene Therapy for Vision Loss

jackiewe October 9, 2019 Hot Topics in Research

AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression

Ding, K., Shen, J., Hafiz, Z., Hackett, S. F., Lima, e. S., Khan, M., . . . Campochiaro, P. A. (2019). AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression. The Journal of Clinical Investigation, https://doi.org/10.1172/JCI129085

There has been great progress in ocular gene therapy, but delivery of viral vectors to the retinal pigmented epithelium (RPE) and retina can be challenging. Subretinal injection, the preferred route of delivery for most applications, requires a surgical procedure that has risks. Herein we report a novel gene therapy delivery approach, suprachoroidal injection of AAV8 vectors, which is less invasive and could be done in an outpatient setting. Two weeks after suprachoroidal injection of AAV8.GFP in rats, GFP fluorescence covered 18.9% of RPE flat mounts and extended entirely around sagittal and transverse sections in RPE and photoreceptors. After 2 suprachoroidal injections of AAV8.GFP, GFP fluorescence covered 30.5% of RPE flat mounts. Similarly, widespread expression of GFP occurred in nonhuman primate and pig eyes after suprachoroidal injection of AAV8.GFP. Compared with subretinal injection in rats of RGX-314, an AAV8 vector expressing an anti-VEGF Fab, suprachoroidal injection of the same dose of RGX-314 resulted in similar expression of anti-VEGF Fab and similar suppression of VEGF-induced vascular leakage. Suprachoroidal AAV8 vector injection provides a noninvasive outpatient procedure to obtain widespread transgene expression in retina and RPE.

Hot Topics: New Factors Could Reverse Arterial Plaque Buildup

jackiewe October 2, 2019 Cardiology, Hot Topics in Research

Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis

Chen, P., Qin, L., Li, G., Wang, Z., Dahlman, J. E., Malagon-Lopez, J., . . . Simons, M. (2019). Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis. Nature Metabolism, http://doi.org/10.1038/s42255-019-0102-3

Atherosclerosis is a progressive vascular disease triggered by interplay between abnormal shear stress and endothelial lipid retention. A combination of these and, potentially, other factors leads to a chronic inflammatory response in the vessel wall, which is thought to be responsible for disease progression characterized by a buildup of atherosclerotic plaques. Yet molecular events responsible for maintenance of plaque inflammation and plaque growth have not been fully defined. Here we show that endothelial transforming growh factor β (TGF-β) signalling is one of the primary drivers of atherosclerosis-associated vascular inflammation. Inhibition of endothelial TGF-β signalling in hyperlipidemic mice reduces vessel wall inflammation and vascular permeability and leads to arrest of disease progression and regression of established lesions. These proinflammatory effects of endothelial TGF-β signalling are in stark contrast with its effects in other cell types and identify it as an important driver of atherosclerotic plaque growth and show the potential of cell-type-specific therapeutic intervention aimed at control of this disease.

Hot Topics: Cannabis Use in Teen Cancer Patients Increasing

jackiewe September 25, 2019 Hot Topics in Research, Oncology

Cannabis Use in Young Adult Cancer Patients

Donovan, K. A., Oberoi-Jassal, R., Chang, Y. D., Rajasekhara, S., Haas, M. F., Randich, A. L., & Portman, D. G. (2019). Cannabis use in young adult cancer patients. Journal of Adolescent and Young Adult Oncology, http://doi.org/10.1089/jayao.2019.0039

Background: The use of cannabis by young adult (YA) cancer patients is likely to increase as medical cannabis becomes more available. Clinically relevant data on cannabis use are needed to establish benchmarks for use, to identify patients who are more likely to use cannabis, and to assess outcomes associated with use.

Objective: The current study sought to determine the rate of cannabis use in YA cancer patients ages 18 to 39, identify demographic and clinical correlates of use, and examine differences in moderate-to-severe symptoms between users and nonusers.

Methods: We conducted a retrospective review of objectively measured tetrahydrocannabinol (THC), self-reported cannabis use, and cancer-related symptomatology in YA cancer patients in active treatment referred for comprehensive supportive care.

Results: Approximately 30% of YA cancer patients tested positive for THC on urine drug testing. At the univariate level, cannabis users were more likely to be male, to have a lifetime history of smoking at least 100 cigarettes, and to be more recently diagnosed. Cannabis use was associated with moderate-to-severe symptomatology, including pain, nausea, lack of appetite, constipation, difficulty sleeping, and poorer overall well-being.

Conclusions: YAs referred for comprehensive supportive care may be managing their cancer-related symptoms with cannabis. Further research is needed to better understand patients’ perceptions of cannabis’s therapeutic and adverse effects, in patients who used cannabis before diagnosis, and in patients who commenced use in response to a cancer diagnosis.

Hot Topics: Genetic Testing Can Use Placental Swab

jackiewe September 18, 2019 Hot Topics in Research, Obstetrics and Gynecology, Pediatrics

A Rapid Method for Label-Free Enrichment of Rare Trophoblast Cells from Cervical Samples

Bailey-Hytholt, C., Sayeed, S., Kraus, M., Joseph, R., Shukla, A., & Tripathi, A. (2019). A rapid method for label-free enrichment of rare trophoblast cells from cervical samples. Scientific Reports, 9(1), 12115. http://doi.org/10.1038/s41598-019-48346-3

Extravillous trophoblasts (EVTs) have the potential to provide the entire fetal genome for prenatal testing. Previous studies have demonstrated the presence of EVTs in the cervical canal and the ability to retrieve a small quantity of these cells by cervical sampling. However, these small quantities of trophoblasts are far outnumbered by the population of cervical cells in the sample, making isolation of the trophoblasts challenging. We have developed a method to enrich trophoblast cells from a cervical sample using differential settling of the cells in polystyrene wells. We tested the addition of small quantities of JEG-3 trophoblast cell line cells into clinical samples from standard Pap tests taken at 5 to 20 weeks of gestation to determine the optimal work flow. We observed that a 4 min incubation in the capture wells led to a maximum in JEG-3 cell settling on the surface (71 ± 10% of the initial amount added) with the removal of 91 ± 3% of the cervical cell population, leading to a 700% enrichment in JEG-3 cells. We hypothesized that settling of mucus in the cervical sample affects the separation. Finally, we performed a proof-of-concept study using our work flow and CyteFinder cell picking to verify enrichment and pick individual JEG-3 and trophoblast cells free of cervical cells. Ultimately, this work provides a rapid, facile, and cost-effective method for enriching native trophoblasts from cervical samples for use in subsequent non-invasive prenatal testing using methods including single cell picking.

Hot Topics: Eye Imaging Enhanced by Machine Learning

jackiewe September 11, 2019 Hot Topics in Research, Radiology

Optical coherence refraction tomography

Zhou, K. C., Qian, R., Degan, S., Farsiu, S., & Izatt, J. A. (2019). Optical coherence refraction tomography. Nature Photonics, http://doi.org/10.1038/s41566-019-0508-1

Optical coherence tomography (OCT) is a cross-sectional, micrometre-scale imaging modality with widespread clinical application. Typical OCT systems sacrifice lateral resolution to achieve long depths of focus for bulk tissue imaging, and therefore tend to have better axial than lateral resolution. Such anisotropic resolution can obscure fine ultrastructural features. Furthermore, conventional OCT suffers from refraction-induced image distortions. Here, we introduce optical coherence refraction tomography (OCRT), which extends the superior axial resolution to the lateral dimension, synthesizing undistorted cross-sectional image reconstructions from multiple conventional images acquired with angular diversity. In correcting refraction-induced distortions to register the OCT images, OCRT also achieves spatially resolved refractive index imaging. We demonstrate greater than threefold improvement in lateral resolution as well as speckle reduction in imaging the tissue ultrastructure, consistent with histology. With further optimization in optical designs to incorporate angular diversity into clinical instruments, OCRT could be widely applied as an enhancement over conventional OCT.

Hot Topics: Community Organizations Can Improve Healthcare

jackiewe August 28, 2019 Family Medicine, Hot Topics in Research

Transforming community well-being through patients’ lived experiences

Gallan AS, McColl-Kennedy JR, Barakshina T, et al. Transforming community well-being through patients’ lived experiences. Journal of Business Research. 2019;100:376-391. https://doi.org/10.1016/j.jbusres.2018.12.029.

The purpose of this article is to (1) explicate micro-to-meso linkages of well-being, (2) provide a theoretical framework to guide research on connecting patient experiences to community well-being, and (3) offer guidelines to policymakers. We develop a conceptual framework establishing connections between micro and meso levels through the expansion of patients’ lived ecosystems. We introduce the concept of patient ecosystem management (PEM), an organizational process that focuses on treating patients differently in terms of assessing, managing, and expanding resources to achieve patient health and well-beinggoals. This process establishes a foundational perspective that is necessary to connect patients’ ecosystems and to facilitate community well-being. Theoretically, this research creates ties between micro-level interactions and a collective measure (community well-being). Policymakers and healthcare professionals should take a PEM perspective, which will require new roles and behaviors, and leverage technology to expand and overlap patients’ individual service ecosystems (intra-alignment), thus enlarging community well-being (inter-alignment).

Hot Topics: Group Medical Visits Effective for Chronic Conditions

jackiewe August 21, 2019 Alternative and Complementary Medicine, Hot Topics in Research, Uncategorized

Characteristics and Components of Medical Group Visits for Chronic Health Conditions: A Systematic Scoping Review

Parikh M, Rajendran I, D’Amico S, Luo M, Gardiner P. Characteristics and components of medical group visits for chronic health conditions: A systematic scoping review. The Journal of Alternative and Complementary Medicine. 2019;25(7):683-698. https://doi.org/10.1089/acm.2018.0524.

Objectives: Chronic health conditions are a major challenge to the health care system. Medical Group Visits (MGVs) are a valuable health care delivery model used in a variety of medical settings and patient populations. We conducted a systematic scoping review of MGV research literature for chronic health conditions to summarize the characteristics and individual components of MGVs in the United States of America and Canada.

Design: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses scoping review methodology and searched five databases using nine widely used MGV-related terms.

Subjects: We included studies conducted in the United States and Canada, whose participants were >18 years old and attended an MGV conducted in a medical setting by a billable health care provider. We excluded groups related to diabetes, pregnancy, and cancer.

Results: Of 3777 studies identified, we found 55 eligible studies of which 9 are randomized controlled trials and 46 are observational studies. The majority of studies were conducted in academic medical centers, were observational in design, and recruited patients using physician referrals. The three most frequently studied groups include a combination of several chronic conditions (n = 12), chronic pain conditions (n = 10), and cardiovascular disease (n = 9). Curriculum components included didactics (n = 55), experiential activities (n = 27), and socializing components (n = 12). Didactic areas include (1) medical topics such as symptoms management (n = 27) of which 14 included pain management, and (2) lifestyle/educational component (n = 33) that comprised of talks on nutrition (n = 29), exercise (n = 20), stress (n = 16), and sleep (n = 10). The top integrative medicine (IM) modalities (n = 13) included: mindfulness techniques (n = 8), meditation (n = 6), and yoga (n = 5). Substantial heterogeneity was observed in the recruitment, implementation, curriculum components, and outcomes reported.

Conclusion: The MGV is a model of patient-centered care that has captured the attention of researchers. IM modalities are well represented in the curriculum components of MGVs. Further investigation into the components identified by this study, may help in better targeting of group interventions to patients and contexts, where it is most likely to be effective.

Hot Topics: Liver Cell Could Regenerate Tissue

jackiewe August 14, 2019 Gastroenterology, Hot Topics in Research

Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors

Segal JM, Kent D, Wesche DJ, et al. Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors. Nature Communications. 2019;10(1):3350. https://doi.org/10.1038/s41467-019-11266-x.

The liver parenchyma is composed of hepatocytes and bile duct epithelial cells (BECs). Controversy exists regarding the cellular origin of human liver parenchymal tissue generation during embryonic development, homeostasis or repair. Here we report the existence of a hepatobiliary hybrid progenitor (HHyP) population in human foetal liver using single-cell RNA sequencing. HHyPs are anatomically restricted to the ductal plate of foetal liver and maintain a transcriptional profile distinct from foetal hepatocytes, mature hepatocytes and mature BECs. In addition, molecular heterogeneity within the EpCAM⁺ population of freshly isolated foetal and adult human liver identifies diverse gene expression signatures of hepatic and biliary lineage potential. Finally, we FACS isolate foetal HHyPs and confirm their hybrid progenitor phenotype in vivo. Our study suggests that hepatobiliary progenitor cells previously identified in mice also exist in humans, and can be distinguished from other parenchymal populations, including mature BECs, by distinct gene expression profiles.

Hot Topics: Autism Linked to High Estrogen in Womb

jackiewe August 7, 2019 Developmental Disorders, Hot Topics in Research, Psychology and Psychiatry

Foetal oestrogens and autism

Baron-Cohen S, Tsompanidis A, Auyeung B, et al. Foetal oestrogens and autism. Mol Psychiatry. 2019. https://doi.org/10.1038/s41380-019-0454-9.

Elevated latent prenatal steroidogenic activity has been found in the amniotic fluid of autistic boys, based on measuring prenatal androgens and other steroid hormones. To date, it is unclear if other prenatal steroids also contribute to autism likelihood. Prenatal oestrogens need to be investigated, as they play a key role in synaptogenesis and corticogenesis during prenatal development, in both males and females. Here we test whether levels of prenatal oestriol, oestradiol, oestrone and oestrone sulphate in amniotic fluid are associated with autism, in the same Danish Historic Birth Cohort, in which prenatal androgens were measured, using univariate logistic regression (n= 98 cases, n= 177 controls). We also make a like-to-like comparison between the prenatal oestrogens and androgens. Oestradiol, oestrone, oestriol and progesterone each related to autism in univariate analyses after correction with false discovery rate. A comparison of standardised odds ratios showed that oestradiol, oestrone and progesterone had the largest effects on autism likelihood. These results for the first time show that prenatal oestrogens contribute to autism likelihood, extending the finding of elevated prenatal steroidogenic activity in autism. This likely affects sexual differentiation, brain development and function.

Hot Topics: Neurotoxin Targets Malaria Mosquitos

jackiewe July 31, 2019 Hot Topics in Research, Infectious Disease

A neurotoxin that specifically targets Anopheles mosquitoes

Contreras E, Masuyer G, Qureshi N, et al. A neurotoxin that specifically targets anopheles mosquitoes. Nature Communications. 2019;10(1):2869. https://doi.org/10.1038/s41467-019-10732-w.

Clostridial neurotoxins, including tetanus and botulinum neurotoxins, generally target vertebrates. We show here that this family of toxins has a much broader host spectrum, by identifying PMP1, a clostridial-like neurotoxin that selectively targets anopheline mosquitoes. Isolation of PMP1 from Paraclostridium bifermentans strains collected in anopheline endemic areas on two continents indicates it is widely distributed. The toxin likely evolved from an ancestral form that targets the nervous system of similar organisms, using a common mechanism that disrupts SNARE-mediated exocytosis. It cleaves the mosquito syntaxin and employs a unique receptor recognition strategy. Our research has an important impact on the study of the evolution of clostridial neurotoxins and provides the basis for the use of P. bifermentans strains and PMP1 as innovative, environmentally friendly approaches to reduce malaria through anopheline control.

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