Publications by authors named "Karen Chen"

131 Publications

Pathway Preferential Estrogens Prevent Hepatosteatosis Due to Ovariectomy and High-Fat Diets.

Nutrients 2021 Sep 23;13(10). Epub 2021 Sep 23.

Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

About 20-30% of premenopausal women have metabolic syndrome, and the number is almost double in postmenopausal women, and these women have an increased risk of hepatosteatosis. Postmenopausal women with metabolic syndrome are often treated with hormone replacement therapy (HRT), but estrogens in currently available HRTs increase the risk of breast and endometrial cancers and Cardiovascular Disease. Therefore, there is a critical need to find safer alternatives to HRT to improve postmenopausal metabolic health. Pathway preferential estrogen 1 (PaPE-1) is a novel estrogen receptor ligand that has been shown to favorably affect metabolic tissues without adverse effects on reproductive tissues. In this study, we have examined the effects of PaPE-1 on metabolic health, in particular, examining its effects on the liver transcriptome and on plasma metabolites in two different mouse models: diet-induced obesity (DIO) and leptin-deficient (ob/ob) mice. PaPE-1 significantly decreased liver weight and lipid accumulation in both DIO and ob/ob models and lowered the expression of genes associated with fatty acid metabolism and collagen deposition. In addition, PaPE-1 significantly increased the expression of mitochondrial genes, particularly ones associated with the electron transport chain, suggesting an increase in energy expenditure. Integrated pathway analysis using transcriptomics and metabolomics data showed that PaPE-1 treatment lowered inflammation, collagen deposition, and pathways regulating fatty acid metabolism and increased metabolites associated with glutathione metabolism. Overall, our findings support a beneficial metabolic role for PaPE-1 and suggest that PaPE-1 may protect postmenopausal women from fatty liver disease without increasing reproductive cancer risk.
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http://dx.doi.org/10.3390/nu13103334DOI Listing
September 2021

Chronic Graft-Versus-Host Disease, Non-Relapse Mortality and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A CIBMTR Analysis.

Transplant Cell Ther 2021 Oct 9. Epub 2021 Oct 9.

CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; Fred Hutchinson Cancer Research Center, Seattle, WA.

Background: The effect of chronic graft-versus-host disease (cGVHD) on the risk of non-relapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (≥60 years).

Methods: We included 4429 adults ≥40 years who received first HLA-matched peripheral blood alloHCT for acute myeloid leukemia or myelodysplastic syndrome between the years 2008-2017. We compared outcomes of 4 groups: older adults (≥60 years) and younger adults (40-59 years) with or without cGVHD to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse and overall survival (OS). We treated cGVHD as a time-dependent covariate. Severity of cGVHD was based on the CIBMTR clinical definitions.

Results: cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher among older versus younger adults. Adults who developed cGVHD as a group had longer OS, compared to age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild and moderate cGVHD were associated with longer OS.

Conclusions: Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse and longer OS. Older adults had a higher risk of NRM but the increased risk of NRM associated with cGVHD did not differ based on age. Development of mild-moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing relapses. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important.
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http://dx.doi.org/10.1016/j.jtct.2021.10.002DOI Listing
October 2021

Low profile sheaths in pediatric neurointervention: a multicenter experience.

J Neurointerv Surg 2021 Oct 8. Epub 2021 Oct 8.

Radiology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, USA.

Background: Pediatric neurointervention is challenged by the appropriateness of adult catheters and devices. This multicenter report on the smallest groin access sheaths offers technical notes and clinical outcomes in the pediatric neurointerventional population.

Methods: All pediatric neurointerventional cases from 2019 to 2021 were reviewed for use of a 3.3F Pediavascular or a 4F Merit Prelude Ideal low profile sheath. Hospital records were reviewed for complications and technical notes and compared with arterial groin access with the 4F Terumo Pinnacle in infants less than 1 year old, before the low profile sheaths at one author's institution were introduced.

Results: From January 1, 2019 to March 31, 2021 there were 347 procedures performed at Boston Children's Hospital and University of Wisconsin. Forty-four procedures in 26 patients were identified in which a 3.3F (38 cases, 20 patients) or 4F (6 cases, 6 patients) sheath was used. The average age was 2.2 years (1.5 days to 18 years). Retinoblastoma intra-arterial chemotherapy infusion (18 of 44) was the most common indication. The remaining procedures comprised vein of Galen embolization (12), diagnostic cerebral angiography (13), and one preoperative tumor embolization. Morbidity included a groin hematoma and decreased pulses (4.5%). No major groin complications occurred. There was no statistically significant difference compared with the historical cohort (132 procedures), which had seven instances of decreased pulses (5.3%, p>0.05).

Conclusion: The 3.3F Pediavascular and 4F Merit Prelude Ideal sheaths are easily incorporated into the pediatric neurointerventionalist's armamentarium for infants and readily accommodate various microcatheters for distal embolization and catheterization.
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http://dx.doi.org/10.1136/neurintsurg-2021-017936DOI Listing
October 2021

An adapted European LeukemiaNet genetic risk stratification for acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplant. A CIBMTR analysis.

Bone Marrow Transplant 2021 Sep 28. Epub 2021 Sep 28.

Division of Hematology/BMT, Mayo Clinic, Rochester, MN, USA.

Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes in acute myeloid leukemia (AML) but data assessing the prognostic value of combined genetic models in the HCT setting are limited. We developed an adapted European LeukemiaNet (aELN) risk classification based on available genetic data reported to the Center for International Blood and Marrow Transplant Research, to predict post-transplant outcomes in 2289 adult AML patients transplanted in first remission, between 2013 and 2017. Patients were stratified according to aELN into three groups: favorable (Fav, N = 181), intermediate (IM, N = 1185), and adverse (Adv, N = 923). Univariate analysis demonstrated significant differences in 2-year overall survival (OS) (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p < 0.001); disease-free survival (DFS) (Fav: 57.8%, IM: 55.5% and Adv: 45.3; p < 0.001) and relapse (Fav: 28%, IM: 27.5% and Adv: 37.5%; p < 0.001). Multivariate analysis (MVA) revealed no differences in outcomes between the Fav and IM groups, thus they were combined. On MVA, patients in the Adv risk group had the highest risk of relapse (HR 1.47 p ≤ 0.001) and inferior DFS (HR 1.35 p < 0.001) and OS (HR 1.39 p < 0.001), even using myeloablative conditioning or in those without the pre-HCT measurable-residual disease. Novel approaches to mitigate relapse in this high-risk group are urgently needed.
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http://dx.doi.org/10.1038/s41409-021-01450-3DOI Listing
September 2021

Supramolecular host-guest hyaluronic acid hydrogels enhance corneal wound healing through dynamic spatiotemporal effects.

Ocul Surf 2021 Sep 16. Epub 2021 Sep 16.

Ophthalmology, Byers Eye Institute at Stanford University School of Medicine, Palo Alto, CA, United States; Chemical Engineering, Stanford University, Palo Alto, CA, United States; VA Palo Alto HealthCare System, Palo Alto, CA, United States. Electronic address:

Large abrasions and deeper ulcers of the cornea can lead to corneal scarring, ulceration and thinning if not promptly and adequately treated. Hyaluronic acid (HA) has been investigated for the treatment of corneal wounds due to its remarkable biocompatibility, transparency and mucoadhesive properties. However, intact linear HA has low retention time on the cornea and chemical crosslinkers to synthesize HA hydrogels can cause toxicity limiting their clinical ocular applications. Here, we used supramolecular HA hydrogels formed by non-covalent host-guest interactions between HA-cyclodextrin and HA-adamantane to evaluate the impact of the hydrogels on corneal wound healing. Supramolecular HA hydrogels facilitated adhesion and spreading of encapsulated human corneal epithelial cells ex vivo and improved corneal wound healing in vivo as an in situ-formed, acellular therapeutic membrane. The HA hydrogels were absorbed within the corneal stroma over time, modulated mesenchymal cornea stromal cell secretome production, reduced cellularity and inflammation of the anterior stroma, and significantly mitigated corneal edema compared to treatment with linear HA and untreated control eyes. Taken together, our results demonstrate supramolecular HA hydrogels as a promising and versatile biomaterial platform for corneal wound healing.
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http://dx.doi.org/10.1016/j.jtos.2021.09.002DOI Listing
September 2021

Usage of a Web-Based Workplace and Symptom Self-Management Intervention Tool to Improve Work Ability for Breast Cancer Survivors.

J Cancer Educ 2021 Sep 3. Epub 2021 Sep 3.

Department of Medicine, School of Medicine and Public Health, 6057 Wisconsin Institute Medical Research, 1111 Highland Ave, Madison, WI, 53705, USA.

This work aimed to evaluate the usage of a web-based intervention (WISE: Work ability Improvement through Symptom and Ergonomic strategies) developed to improve work ability for women recently diagnosed with breast cancer. Twenty-two women undergoing adjuvant treatment for breast cancer were provided access to WISE. This website includes content pages (e.g., information on ergonomics, symptom management, and other work-related resources) and worksheets (e.g., journals to track symptoms or goals). It could be personalized based on individual work activities and symptoms. Measures assessed at 3 months included usage of the website and perceived usefulness. Thirteen of the 22 participants (60%) accessed WISE; 11 personalized their information. Content and worksheet pages had 97 and 79 visits, respectively. Most frequently visited pages were "setting goals" (i.e., prioritize and track symptoms; 45 visits) and "steps to creating your WISE plan" (i.e., incorporate symptom and ergonomic strategies; 16 visits). Median duration time was 11.05 (range 0.35-79.55) minutes. Usefulness of the content and worksheet pages assessed via a 7-point Likert scale (1 = strongly disagree, 7 = strongly agree) was 5.08 (SD = 1.59) and 4.26 (SD = 2.03), respectively. Participants were likely to recommend WISE to other women undergoing cancer treatment (mean = 6.11; SD = 1.05). The majority of participants personalized WISE work and symptom strategies. Overall, participants agreed that WISE content pages were useful and would recommend WISE for other breast cancer survivors. Results support that majority of breast cancer survivors, undergoing treatment with curative intent, accessed a web-based intervention that provided personalized information on workplace and symptom strategies.
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http://dx.doi.org/10.1007/s13187-021-02048-5DOI Listing
September 2021

Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study.

Front Immunol 2021;12:709861. Epub 2021 Aug 12.

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Background: Immune hyperactivity is an important contributing factor to the morbidity and mortality of COVID-19 infection. Nasal administration of anti-CD3 monoclonal antibody downregulates hyperactive immune responses in animal models of autoimmunity through its immunomodulatory properties. We performed a randomized pilot study of fully-human nasal anti-CD3 (Foralumab) in patients with mild to moderate COVID-19 to determine if its immunomodulatory properties had ameliorating effects on disease.

Methods: Thirty-nine outpatients with mild to moderate COVID-19 were recruited at Santa Casa de Misericordia de Santos in Sao Paulo State, Brazil. Patients were randomized to three cohorts: 1) Control, no Foralumab (n=16); 2) Nasal Foralumab (100ug/day) given for 10 consecutive days with 6 mg dexamethasone given on days 1-3 (n=11); and 3) Nasal Foralumab alone (100ug/day) given for 10 consecutive days (n=12). Patients continued standard of care medication.

Results: We observed reduction of serum IL-6 and C-reactive protein in Foralumab alone . untreated or Foralumab/Dexa treated patients. More rapid clearance of lung infiltrates as measured by chest CT was observed in Foralumab and Foralumab/Dexa treated subjects . those that did not receive Foralumab. Foralumab treatment was well-tolerated with no severe adverse events.

Conclusions: This pilot study suggests that nasal Foralumab is well tolerated and may be of benefit in treatment of immune hyperactivity and lung involvement in COVID-19 disease and that further studies are warranted.
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http://dx.doi.org/10.3389/fimmu.2021.709861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406802PMC
September 2021

SMN protein is required throughout life to prevent spinal muscular atrophy disease progression.

Hum Mol Genet 2021 Aug 9. Epub 2021 Aug 9.

PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.

Spinal muscular atrophy (SMA) is caused by the loss of the survival motor neuron 1 (SMN1) gene function. The related SMN2 gene partially compensates but produces insufficient levels of SMN protein due to alternative splicing of exon 7. Evrysdi™ (risdiplam), recently approved for the treatment of SMA, and related compounds promote exon 7 inclusion to generate full-length SMN2 mRNA and increase SMN protein levels. SMNΔ7 type I SMA mice survive without treatment for ~ 17 days. SMN2 mRNA splicing modulators increase survival of SMN∆7 mice with treatment initiated at postnatal day 3 (PND3). To define SMN requirements for adult mice, SMNΔ7 mice were dosed with a SMN2 mRNA splicing modifier from PND3 to PND40, then dosing was stopped. Mice not treated after PND40 showed progressive weight loss, necrosis, and muscle atrophy after ~ 20 days. Male mice presented a more severe phenotype than female mice. Mice dosed continuously did not show disease symptoms. The estimated half-life of SMN protein is 2 days indicating that the SMA phenotype reappeared after SMN protein levels returned to baseline. Although SMN protein levels decreased with age in mice and SMN protein levels were higher in brain than in muscle, our studies suggest that SMN protein is required throughout the life of the mouse and is especially essential in adult peripheral tissues including muscle. These studies indicate that drugs such as risdiplam will be optimally therapeutic when given as early as possible after diagnosis and potentially will be required for the life of an SMA patient.
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http://dx.doi.org/10.1093/hmg/ddab220DOI Listing
August 2021

Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA).

Int J Mol Sci 2021 Jul 27;22(15). Epub 2021 Jul 27.

Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.

Spinal muscular atrophy (SMA) is a motor neuron disease caused by insufficient levels of the survival motor neuron (SMN) protein. One of the most prominent pathological characteristics of SMA involves defects of the neuromuscular junction (NMJ), such as denervation and reduced clustering of acetylcholine receptors (AChRs). Recent studies suggest that upregulation of agrin, a crucial NMJ organizer promoting AChR clustering, can improve NMJ innervation and reduce muscle atrophy in the delta7 mouse model of SMA. To test whether the muscle-specific kinase (MuSK), part of the agrin receptor complex, also plays a beneficial role in SMA, we treated the delta7 SMA mice with an agonist antibody to MuSK. MuSK agonist antibody #13, which binds to the NMJ, significantly improved innervation and synaptic efficacy in denervation-vulnerable muscles. MuSK agonist antibody #13 also significantly increased the muscle cross-sectional area and myofiber numbers in these denervation-vulnerable muscles but not in denervation-resistant muscles. Although MuSK agonist antibody #13 did not affect the body weight, our study suggests that preservation of NMJ innervation by the activation of MuSK may serve as a complementary therapy to SMN-enhancing drugs to maximize the therapeutic effectiveness for all types of SMA patients.
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http://dx.doi.org/10.3390/ijms22158015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348537PMC
July 2021

Mechanical thrombectomy beyond the circle of Willis: efficacy and safety of different techniques for M2 occlusions.

J Neurointerv Surg 2021 Jul 5. Epub 2021 Jul 5.

Department of Neurosurgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Background: M2 segment occlusions represent approximately one-third of non-lacunar ischemic stroke and can lead to permanent neurological deficits. Various techniques are available for mechanical thrombectomy beyond the circle of Willis, but data evaluating their effectiveness and safety are lacking.

Methods: A retrospective review of patients with ischemic stroke undergoing mechanical thrombectomy for M2 occlusions from 13 centers in North American and Europe was performed. Tandem or multiple-territory occlusions were excluded. The primary outcome was 90-day modified Rankin Scale and reperfusion rates across stent-retriever, direct aspiration and combined techniques.

Results: There were 465 patients (mean age 71.48±14.03 years, 53.1% female) with M2 occlusions who underwent mechanical thrombectomy. Stent-retriever alone was used in 133 (28.6%), direct aspiration alone in 93 (20.0%) and the combined technique in 239 (51.4%) patients. Successful reperfusion was achieved with the combined technique in 198 (82.2%; OR 2.6 (1.1-6.9)), with stent-retriever alone in 112 (84.2%; OR 9.2 (1.9-44.6)) and with direct aspiration alone in 62 (66.7%; referencecategory). Intraprocedural subarachnoid hemorrhages (iSAH) were 36 (7.7%) and were more likely to occur in patients treated with the stent-retrievers (OR 5.0 (1.1-24.3)) and combined technique (OR 4.6 (1.1-20.9)). Good clinical outcome was achieved in 260 (61.8%) patients, while 59 (14.0%) patients died. Older age, higher baseline NIHSS (National Institutes of Health Stroke Scale), parenchymal hemorrhage and iSAH were associated with poor outcome while successful recanalization and higher baseline ASPECTS (Alberta Stroke Program Early CT Score) were associated with good outcome. No differences were found among the three techniques in terms of clinical outcome.

Conclusion: Stent-retrievers and a combined approach for M2 occlusions seem more effective than direct aspiration, but with higher rates of iSAH. This leads to no detectable difference in clinical outcome at 3 months.
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http://dx.doi.org/10.1136/neurintsurg-2021-017425DOI Listing
July 2021

Endovascular Intervention for Refractory Pediatric Cerebral Venous Sinus Thrombosis.

Pediatr Neurol 2021 Aug 11;121:45-50. Epub 2021 May 11.

Department of Neurosurgery, University of Texas Medical Branch, Galveston, Texas. Electronic address:

Background: Cerebral venous sinus thrombosis (CVST) is a rare but potentially morbid disease in the pediatric population, and the optimal treatment is not fully understood. Endovascular intervention for this condition has been rarely reported.

Methods: The Stroke Thrombectomy and Aneurysm Registry was queried for patients aged less than or equal to 18 years undergoing endovascular treatment for CVST in the past 10 years. Clinical charts and radiographic data were retrospectively reviewed. Modified Rankin Score (mRS) at 90 days postprocedure was determined as the primary outcome.

Results: A total of seven patients across five pediatric centers ranging from 7 to 16 years of age were identified with a mean follow-up of 28 months. All had underlying conditions predisposing to CVST. Endovascular intervention was undertaken due to neurological deterioration despite systemic anticoagulation; venous infarct was evident preoperatively in six of seven patients. Mechanical venous thrombectomy was attempted in all individuals, and intrasinus thrombolytic therapy was also performed in three cases. Six patients had favorable outcome with mRS 0 or 1 at 90 days postprocedure; one remained neurologically devastated.

Conclusions: Endovascular treatment by an experienced interventionalist may be safe and effective in severe cases of CVST in children failing frontline therapy. Children with radiographic or clinical progression despite anticoagulation may be considered for endovascular intervention in a timely manner.
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http://dx.doi.org/10.1016/j.pediatrneurol.2021.05.004DOI Listing
August 2021

Prolonged Response to HER2-Directed Therapy in Three Patients with HER2-Amplified Metastatic Carcinoma of the Biliary System: Case Study and Review of the Literature.

Oncologist 2021 08 11;26(8):640-646. Epub 2021 May 11.

Division of Hematology and Oncology, Columbia University Irving Medical Center and New York Presbyterian Hospital, New York, New York, USA.

HER2 amplification, which results in overexpression of the receptor tyrosine kinase HER2, has been described in a wide variety of malignancies. HER2-targeting agents have been incorporated into the treatment paradigms for HER2-overexpressing breast and gastric cancer. More recently, these agents have shown promise in other gastrointestinal malignancies, such as colon cancer and biliary tract tumors. This study discusses two patients with gallbladder carcinoma and a third with ampullary carcinoma who were able to achieve marked responses to HER2-directed therapy. These cases underscore the importance of molecular analysis for HER2 amplification/HER2 overexpression, irrespective of tumor histology, and highlight a need for further investigation of HER2-directed therapy beyond breast and gastroesophageal cancers. KEY POINTS: Current guidelines recommend molecular assessment for HER2 overexpression exclusively in breast and gastric adenocarcinoma. The focus of this report is on three cases (two biliary tract and one ampullary carcinoma) in which amplification of HER2 or overexpression of HER2 was detected and treatment with HER2-directed therapy resulted in robust responses. These cases exemplify responsiveness of non-breast/gastric histologies to HER2-directed therapies, highlighting several promising new settings for these agents. Testing for amplification of HER2 or overexpression of HER2 should be considered especially in rare diseases with limited treatment options.
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http://dx.doi.org/10.1002/onco.13800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342570PMC
August 2021

Task-Oriented and Imitation-Oriented Movements in Virtual Reality Exercise Performance and Design.

Hum Factors 2021 Apr 19:187208211010100. Epub 2021 Apr 19.

6798 North Carolina State University, Raleigh, USA.

Objective: This study investigated the influence of game features and practice type on human kinematic and muscular performance in a virtual reality exercise (VRE). Participants demonstrated changes in shoulder flexion angle and muscle activation under different virtual scenarios.

Background: Conventional VRE studies often compared the outcomes between an experimental group that underwent exercise in VR and a real-world exercise control group, whereas comparisons between VRE programs are lacking. Besides, the attributes of VREs received little attention.

Method: Thirteen able-bodied participants performed upper extremity exercise movements in immersive VR using a head-mounted display. Participants performed task-oriented and imitation-oriented movements with different game features. Shoulder muscle activity (the deltoid, supraspinatus, and infraspinatus) and shoulder motion were collected.

Results: Practice type (task-oriented, imitation-oriented) significantly influenced the flexion angle of the shoulder complex ((1,11) = 9.53, = .01), and the muscle activity of the supraspinatus ((1,9) = 12.61, = .006) and the infraspinatus ((1,9) = 12.71, = .006). Game features did not have a statistically significant effect on shoulder flexion angle or shoulder muscles' activations.

Conclusions: Compared to imitation-oriented practice, task-oriented practice elicited more intensive shoulder movements and muscular efforts but also induced greater movement variations. Substantial differences across game features levels should be further investigated to have significant effects.

Applications: This research may help guide the design of future VREs. For strength training or rehabilitation where intensive practice is required, task-oriented practice should be considered; for movement learning where movement consistency is required, imitation oriented practice should be adopted.
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http://dx.doi.org/10.1177/00187208211010100DOI Listing
April 2021

Results from a prospective longitudinal survey of employment and work outcomes in newly diagnosed cancer patients during and after curative-intent chemotherapy: A Wisconsin Oncology Network study.

Cancer 2021 03 24;127(5):801-808. Epub 2020 Nov 24.

University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.

Background: Postcancer work limitations may affect a substantial proportion of patients and contribute to the "financial toxicity" of cancer treatment. The degree and nature of work limitations and employment outcomes are poorly understood for cancer patients, particularly in the immediate period of transition after active treatment. We prospectively examined employment, work ability, and work limitations during and after treatment.

Methods: A total of 120 patients receiving curative therapy who were employed prior to their cancer diagnosis and who intended to work during or after end of treatment (EOT) completed surveys at baseline (pretreatment), EOT, and 3, 6, and 12 months after EOT. Surveys included measures of employment, work ability, and work limitations. Descriptive statistics (frequencies, percentages, means with standard deviations) were calculated.

Results: A total of 111 participants completed the baseline survey. On average, participants were 48 years of age and were mostly white (95%) and female (82%) with a diagnosis of breast cancer (69%). Full-time employment decreased during therapy (from 88% to 50%) and returned to near prediagnosis levels by 12-month follow-up (78%). Work-related productivity loss due to health was high during treatment.

Conclusions: This study is the first to report the effects of curative intent cancer therapy on employment, work ability, and work limitations both during and after treatment. Perceived work ability was generally high overall 12 months after EOT, although a minority reported persistent difficulty. A prospective analysis of factors (eg, job type, education, symptoms) most associated with work limitations is underway to assist in identifying at-risk patients.
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http://dx.doi.org/10.1002/cncr.33311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945680PMC
March 2021

ACR Appropriateness Criteria® Acute Trauma to the Ankle.

J Am Coll Radiol 2020 Nov;17(11S):S355-S366

Specialty Chair, Mayo Clinic, Phoenix, Arizona.

Acute injuries to the ankle are frequently encountered in the setting of the emergency room, sport, and general practice. This ACR Appropriateness Criteria defines best practices for imaging evaluation for several variants of patients presenting with acute ankle trauma. The variants include scenarios when Ottawa Rules can be evaluated, when there are exclusionary criteria, when Ottawa Rules cannot be evaluated, as well as specific injuries. Clinical scenarios are followed by the imaging choices and their appropriateness with an accompanying narrative explanation to help physicians to order the most appropriate imaging test. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2020.09.014DOI Listing
November 2020

In situ-forming collagen hydrogel crosslinked via multi-functional PEG as a matrix therapy for corneal defects.

Sci Rep 2020 10 7;10(1):16671. Epub 2020 Oct 7.

Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA.

Visually significant corneal injuries and subsequent scarring collectively represent a major global human health challenge, affecting millions of people worldwide. Unfortunately, less than 2% of patients who could benefit from a sight-restoring corneal transplant have access to cadaveric donor corneal tissue. Thus, there is a critical need for new ways to repair corneal defects that drive proper epithelialization and stromal remodeling of the wounded area without the need for cadeveric donor corneas. Emerging therapies to replace the need for donor corneas include pre-formed biosynthetic buttons and in situ-forming matrices that strive to achieve the transparency, biocompatibility, patient comfort, and biointegration that is possible with native tissue. Herein, we report on the development of an in situ-forming hydrogel of collagen type I crosslinked via multi-functional polyethylene glycol (PEG)-N-hydroxysuccinimide (NHS) and characterize its biophysical properties and regenerative capacity both in vitro and in vivo. The hydrogels form under ambient conditions within minutes upon mixing without the need for an external catalyst or trigger such as light or heat, and their transparency, degradability, and stiffness are modulated as a function of number of PEG arms and concentration of PEG. In addition, in situ-forming PEG-collagen hydrogels support the migration and proliferation of corneal epithelial and stromal cells on their surface. In vivo studies in which the hydrogels were formed in situ over stromal keratectomy wounds without sutures showed that they supported multi-layered surface epithelialization. Overall, the in situ forming PEG-collagen hydrogels exhibited physical and biological properties desirable for a corneal stromal defect wound repair matrix that could be applied without the need for sutures or an external trigger such as a catalyst or light energy.
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http://dx.doi.org/10.1038/s41598-020-72978-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542443PMC
October 2020

Pipeline Embolization in Patients with Posterior Circulation Subarachnoid Hemorrhages: Is Takotsubo Cardiomyopathy a Limiting Factor?

World Neurosurg 2020 11 7;143:e523-e528. Epub 2020 Aug 7.

Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah. Electronic address:

Background: Hemorrhagic vascular lesions in the posterior cerebral circulation such as ruptured aneurysms and dissections can be challenging to treat. Flow diversion has become an important off-label option, but few studies have analyzed the safety of these devices in this setting. Using an international, multicenter cohort, we reviewed posterior circulation subarachnoid hemorrhage (SAH) patients treated with the Pipeline Embolization Device (PED) in the acute setting and assessed the incidence of Takotsubo cardiomyopathy (TCM).

Methods: Eleven neurovascular centers were queried to identify cases of posterior circulation aneurysms or dissections treated with the PED in the acute setting of SAH. Among those, 5 centers had cases that matched the inclusion criteria. The following variables were evaluated: demographics, the location and morphology of the aneurysm, the clinical presentation, the specific form of treatment, complications including the development of TCM, antiplatelet medication regimen, and follow-up time.

Results: A total of 23 patients were treated with PED after posterior circulation SAH, and 13% of these developed TCM. The lesions were the result of hemorrhagic intracranial dissection (8 patients), ruptured pseudoaneurysm (3), ruptured saccular aneurysm (7), blister aneurysm (4), and fusiform aneurysm (1). Ninety-one percent of patients had complete or near-complete aneurysm occlusion on follow-up imaging. Five patients died in the perioperative period; 16/18 survivors had a favorable outcome.

Conclusions: We describe an unexpectedly high incidence of TCM after the placement of PEDs in patients with posterior circulation SAH in our large case series. Further studies will be needed to elucidate possible causes.
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http://dx.doi.org/10.1016/j.wneu.2020.08.013DOI Listing
November 2020

Intracranial venous malformations: Incidence and characterization in a large pediatric cohort.

Interv Neuroradiol 2021 Feb 20;27(1):6-15. Epub 2020 Jul 20.

Neurointerventional Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Significant advances have been reported recently in the genetic and mechanistic characterization of extracranial venous malformations. However, intracranial purely venous malformations (icVM) analogous to those outside the CNS have not been systematically described.

Purpose: We sought to ascertain whether such an entity as icVM could in fact be identified, distinct from previously described CNS venous anomalies and analogous to extracranial venous malformations.

Methods: Our prospectively collected pediatric cerebrovascular database was reviewed to identify patients with icVM; 1458 consecutive angiograms and/or angiographic interventions performed on 706 children at our institution from October, 2006 through May, 2019 were evaluated, in addition to outside imaging studies on 192 additional patients sent to our Vascular Anomalies Center for cerebrovascular review during the same time period. Thus, the cohort consisted of 898 children.

Results: Nineteen of 898 patients (2.1%) were found to harbor icVM, including 9 (47.3%) with sinus pericranii, 15 (78.9%) with associated large, complex extracranial venous malformations, and 3 (15.7%) with neurocognitive delay. There was no intracranial hemorrhage or venous hypertension seen in the cohort. Asymptomatic venous thrombosis in the superior sagittal sinus was seen in three patients.

Conclusion: Venous malformations, both extracranial and icVM, share many characteristics that are distinct from developmental venous anomalies. icVM were not associated with venous hypertension. The underlying genetic mutations involved in the development of icVM, germ-line or somatic, remain to be elucidated, but may very well involve shared mechanisms and pathways with extracranial venous malformations.
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http://dx.doi.org/10.1177/1591019920943752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903553PMC
February 2021

Experience With the Pipeline Embolization Device for Posterior Circulations Aneurysms: A Multicenter Cohort Study.

Neurosurgery 2020 Jul 6. Epub 2020 Jul 6.

Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.

Background: The Pipeline Embolization Device (PED; Medtronic) has been used off-label for the treatment of challenging posterior circulation aneurysms. Data on this modality are primarily limited to small retrospective single-center series.

Objective: To assess safety and efficacy of this treatment by establishing an international, multicenter collaboration.

Methods: Consecutive posterior circulation aneurysms treated with the PED from 2012 to 2019 across 11 neurovascular centers were retrospectively reviewed. Baseline demographics, aneurysm and treatment characteristics, complications, occlusion status, and functional outcome were assessed.

Results: There were 149 posterior circulation aneurysms treated with PED in 146 patients. A total of 24 (16.4%) patients presented with subarachnoid hemorrhage. Most aneurysms were dissecting/blister (36.2%) in morphology, followed by saccular (35.6%) and fusiform (28.2%). The most common locations were the vertebral (51.7%) and basilar arteries (22.8%). Complete or near-complete occlusion (>90%) was achieved in 90.9% of aneurysms at a median follow-up of 12 mo. Dissecting/blister aneurysms were most likely to occlude (P = .06). Symptomatic neurologic complications occurred in 9.4% of aneurysms, associated with larger size, ruptured presentation, presentations with brain stem compression, cranial nerve palsy, or stroke. Favorable functional outcome (modified Rankin Score 0-2) was achieved in 86.2% of patients. There were 6 fatalities of which 4 occurred in aneurysmal subarachnoid hemorrhage patients.

Conclusion: This multicenter study shows that PED for the treatment of posterior circulation is preferentially used for the treatment of fusiform and dissecting/blister aneurysm morphologies. Despite the challenges presented by these less-common morphologies, flow diversion may be performed with a neurologic complication rate of about 10% and favorable long-term aneurysm occlusion rates.
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http://dx.doi.org/10.1093/neuros/nyaa277DOI Listing
July 2020

Comparison of PED and FRED flow diverters for posterior circulation aneurysms: a propensity score matched cohort study.

J Neurointerv Surg 2021 Feb 1;13(2):153-158. Epub 2020 Jul 1.

Department of Neuroradiology, Friedrich Alexander University Erlangen Nuremberg Faculty of Medicine, Erlangen, Bayern, Germany.

Background: Flow diversion is a common endovascular treatment for cerebral aneurysms, but studies comparing different types of flow diverters are scarce.

Objective: To perform a propensity score matched cohort study comparing the Pipeline Embolization Device (PED) and Flow Redirection Intraluminal Device (FRED) for posterior circulation aneurysms.

Methods: Consecutive aneurysms of the posterior circulation treated at 25 neurovascular centers with either PED or FRED were collected. Propensity score matching was used to control for age, duration of follow-up imaging, adjunctive coiling, and aneurysm location, size, and morphology; previously ruptured aneurysms were excluded. The two devices were compared for the following outcomes: procedural complications, aneurysm occlusion, and functional outcome.

Results: A total of 375 aneurysms of the posterior circulation were treated in 369 patients. The PED was used in 285 (77.2%) and FRED in 84 (22.8%) procedures. Aneurysms treated with the PED were more commonly fusiform and larger than those treated with FRED. To account for these important differences, propensity score matching was performed resulting in 33 PED and FRED unruptured aneurysm pairs. No differences were found in occlusion status and neurologic thromboembolic or hemorrhagic complications between the two devices. The proportion of patients with favorable functional outcome was higher with FRED (100% vs 87.9%, p=0.04).

Conclusion: Comparative analysis of PED and FRED for the treatment of unruptured posterior circulation aneurysms did not identify significant differences in aneurysm occlusion or neurologic complications. Variations in functional outcomes warrant additional investigations.
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http://dx.doi.org/10.1136/neurintsurg-2020-016055DOI Listing
February 2021

ACR Appropriateness Criteria® Acute Trauma to the Knee.

J Am Coll Radiol 2020 May;17(5S):S12-S25

Specialty Chair, Mayo Clinic, Phoenix, Arizona.

Acute trauma to the knee is a common presentation seen in the emergency department. After a routine clinical examination, imaging is frequently performed to facilitate the diagnosis and almost always starts with radiographs. If clinically indicated, advanced cross-sectional imaging may then be performed for further evaluation. CT is often performed for preoperative planning of the complex tibial plateau and distal femur fractures. Currently, MRI is the study of choice for evaluation of bone marrow, internal derangements, and other soft-tissue injuries about the knee joint. In patients with knee dislocations, MR angiography may be performed simultaneously with MRI for evaluation of internal derangements and vascular injuries with less morbidity compared to conventional angiography. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.
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http://dx.doi.org/10.1016/j.jacr.2020.01.041DOI Listing
May 2020

Concise Synthesis of (+)-[ C ]-Anatoxin-a by Dynamic Kinetic Resolution of a Cyclic Iminium Ion.

Angew Chem Int Ed Engl 2020 07 11;59(28):11364-11368. Epub 2020 May 11.

Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, 93106-9510, USA.

An asymmetric total synthesis of [ C ]-anatoxin-a ([ C ]-1) has been developed from commercially available ethyl [ C ]-acetoacetate ([ C ]-15). The unique requirements associated with isotope incorporation inspired a new, robust, and highly scalable route, providing access to 0.110 g of this internal standard for use in the detection and precise quantification of anatoxin-a in freshwater. A highlight of the synthesis is a method that leverages a cyclic iminium ion racemization to achieve dynamic kinetic resolution in an enantioselective Morita-Baylis-Hillman (MBH) cyclization.
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http://dx.doi.org/10.1002/anie.202004464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409530PMC
July 2020

Endovascular Thrombectomy for Low ASPECTS Large Vessel Occlusion Ischemic Stroke: A Systematic Review and Meta-Analysis.

Can J Neurol Sci 2020 09 17;47(5):612-619. Epub 2020 Apr 17.

Division of Diagnostic and Therapeutic Neuroradiology, Department of Medical Imaging, St. Michael's Hospital, Toronto, ON, Canada.

Background: The current American Heart Association guidelines for acute ischemic stroke reserve Grade 1A recommendation for the use of endovascular thrombectomy (EVT) for patients with an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of ≥6.

Objective: We aim to determine the safety and efficacy of EVT for large vessel occlusion ischemic stroke patients with low ASPECTS (5 or less).

Methods: Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched for studies appraising the outcomes of EVT for low ASPECTS ischemic stroke. A meta-analysis of proportions compared the clinical outcomes of patients undergoing EVT and those receiving best medical therapy only.

Results: Nine studies (1,196 patients) were included. There was a trend (p = 0.11) toward a higher rate of symptomatic intracranial hemorrhage (sICH) in the EVT group (9.2%; 95% CI 6.1-13.6; I2 53.37%) compared to the medical group (5.5%; 95% CI 3.7-8.1; I2 0%). There was no difference (p = 0.41) in the pooled 90-day mortality of EVT patients (30.7%; 95% CI 21.7-41.5; I2 84.23%) and medical patients (36.6%; 95% CI 26.4-48.1; I2 76.2%). EVT patients had better (p = 0.001) 90-day outcomes, with 27.7% (95% CI 21.8-34.5; I2 62.08%) of patients attaining a modified Rankin Scale of 0-2 compared to only 3.7% (95% CI 2.3-5.9; I2 87.21%) in the medical group.

Conclusions: This meta-analysis demonstrates a trend in higher sICH among low ASPECTS patients undergoing EVT. Despite this, a significant proportion of this subset of patients still achieved good functional outcomes at 90 days. Randomized trials are necessary to substantiate this result as significant bias is inherent in the observational studies included in this review.
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http://dx.doi.org/10.1017/cjn.2020.71DOI Listing
September 2020

Endovascular thrombectomy for tandem acute ischemic stroke associated with cervical artery dissection: a systematic review and meta-analysis.

Neuroradiology 2020 Jul 12;62(7):861-866. Epub 2020 Mar 12.

Department of Radiology, Austin Hospital, Melbourne, Australia.

Purpose: Strokes associated with cervical artery dissection have been managed primarily with antithrombotics with poor outcomes. The additive role of endovascular thrombectomy remains unclear. The objective was to perform systematic review and meta-analysis to compare endovascular thrombectomy and medical therapy for acute ischemic stroke associated with cervical artery dissection.

Methods: Studies from six electronic databases included outcomes of patient cohorts with acute ischemic stroke secondary to cervical artery dissection who underwent treatment with endovascular thrombectomy. A meta-analysis of proportions was conducted with a random effects model. Modified Rankin score at 90 days (mRS 0-2) was the primary outcome. Other outcomes included proportion of patients with thrombolysis in cerebral infarction (TICI) 2b-3 flow, 90-day mortality rate, and 90-day symptomatic intracerebral hemorrhage (sICH) rate.

Results: Six studies were included, comprising 193 cases that underwent thrombectomy compared with 59 cases that were managed medically. Successful recanalization with a pooled proportion of thrombolysis in cerebral infarction (TICI) 2b-3 flow in the thrombectomy group was 74%. Favorable outcome (mRS 0-2) was superior in the pooled thrombectomy group (62.9%, 95% CI 55.8-69.5%) compared with medical management (41.5%, 95% CI 29.0-55.1%, P = 0.006). The pooled rate of 90-day mortality was similar for endovascular vs medical (8.6% vs 6.3%). The pooled rate of symptomatic intracranial haemorrhage (sICH) did not significantly differ (5.9% vs 4.2%, P = 0.60).

Conclusions: Current data suggest that endovascular thrombectomy may be an option in patients with acute ischemic stroke due to cervical artery dissection. This requires further confirmation in higher quality prospective studies.
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http://dx.doi.org/10.1007/s00234-020-02388-xDOI Listing
July 2020

Motor neuron loss in SMA is not associated with somal stress-activated JNK/c-Jun signaling.

Hum Mol Genet 2019 10;28(19):3282-3292

Department of Neurology.

A pathological hallmark of spinal muscular atrophy (SMA) is severe motor neuron (MN) loss, which results in muscle weakness and often infantile or childhood mortality. Although it is well established that deficient expression of survival motor neuron (SMN) protein causes SMA, the molecular pathways that execute MN cell death are poorly defined. The c-Jun NH2-terminal kinases (JNKs) are stress-activated kinases with multiple substrates including c-Jun, which can be activated during neuronal injury and neurodegenerative disease leading to neuronal apoptosis. Recently, increased JNK-c-Jun signaling was reported in SMA raising the possibility that JNK inhibitors could be a novel treatment for this disease. We examined JNK-c-Jun activity in SMA mouse and human cultured cells and tissues. Anisomycin treatment of human SMA fibroblasts and sciatic nerve ligation in SMA mice provoked robust phosphorylated-c-Jun (p-c-Jun) expression indicating that SMN-deficiency does not prevent activation of the stress-induced JNK-c-Jun signaling pathway. Despite retained capacity to activate JNK-c-Jun, we observed no basal increase of p-c-Jun levels in SMA compared to control cultured cells, human or mouse spinal cord tissues, or mouse MNs during the period of MN loss in severe SMA model mice. In both controls and SMA, ~50% of α-MN nuclei express p-c-Jun with decreasing expression during the early postnatal period. Together these studies reveal no evidence of stress-activated JNK-c-Jun signaling in MNs of SMA mice or human tissues, but do highlight the important role of JNK-c-Jun activity during normal MN development raising caution about JNK antagonism in this pediatric neuromuscular disease.
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http://dx.doi.org/10.1093/hmg/ddz150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859432PMC
October 2019

Tfap2a is a novel gatekeeper of nephron differentiation during kidney development.

Development 2019 07 10;146(13). Epub 2019 Jul 10.

Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA

Renal functional units known as nephrons undergo patterning events during development that create a segmental array of cellular compartments with discrete physiological identities. Here, from a forward genetic screen using zebrafish, we report the discovery that transcription factor AP-2 alpha () coordinates a gene regulatory network that activates the terminal differentiation program of distal segments in the pronephros. We found that acts downstream of Iroquois homeobox 3b (), a distal lineage transcription factor, to operate a circuit consisting of , and genes encoding solute transporters that dictate the specialized metabolic functions of distal nephron segments. Interestingly, this regulatory node is distinct from other checkpoints of differentiation, such as polarity establishment and ciliogenesis. Thus, our studies reveal insights into the genetic control of differentiation, where is essential for regulating a suite of segment transporter traits at the final tier of zebrafish pronephros ontogeny. These findings have relevance for understanding renal birth defects, as well as efforts to recapitulate nephrogenesis to facilitate drug discovery and regenerative therapies.
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http://dx.doi.org/10.1242/dev.172387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633607PMC
July 2019

A usability assessment of riding lawn-mowing equipment with varying levels of design standards compliance.

Appl Ergon 2019 Jul 21;78:76-85. Epub 2019 Feb 21.

Herbert Wertheim College of Engineering, Department of Industrial and Systems Engineering, University of Florida, 303 Weil Hall / P.O. Box 116595, Gainesville, FL, 32611, United States. Electronic address:

The use of riding lawn equipment (RLE) is related to a significant number of accidents every year. To provide basis for product design and enhance user performance and safety, a usability and performance assessment of modern riding lawn-mowing tractor designs and features was conducted in a real-world test environment. Five current commercially available RLEs were tested with response measures including task performance time and accuracy, physiological workload, system usability scores (SUS), and subjective rankings of RLE models. This data was used to identify sensitivity of responses to variations in RLE design features and functionality. The data was also used to assess the validity of new tractor design standard conformance tool, the RLEval methodology. This tool made comprehensive evaluation of RLE models compliance with over 70 specific design standards and was applied by human factors experts. Experiment results revealed sensitivity of all response measures to design differences among the five RLE models, except the objective workload measures. Response measures including task performance, SUSs and subjective rankings showed partial agreement with the RLEval scores. In general, the study results demonstrated a comprehensive experimental methodology for usability and performance evaluations of RLEs as well as merit of using the RLEval as preliminary method to compare design features. Some aspects of the usability experimentation and the RLEval method appear to be complementary.
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http://dx.doi.org/10.1016/j.apergo.2019.02.003DOI Listing
July 2019

Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance.

Cancers (Basel) 2019 Apr 4;11(4). Epub 2019 Apr 4.

Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.

A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and the nuclear transport protein XPO1 in overcoming endocrine resistance. Selinexor (SEL), an XPO1 antagonist, has been evaluated in multiple late stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Our transcriptomics analysis showed that 4-Hydroxytamoxifen (4-OHT), SEL alone or their combination induced differential Akt signaling- and metabolism-associated gene expression profiles. Western blot analysis in endocrine resistant cell lines and xenograft models validated differential Akt phosphorylation. Using the Seahorse metabolic profiler, we showed that ERα-XPO1 targeting changed the metabolic phenotype of TAM-resistant breast cancer cells from an energetic to a quiescent profile. This finding demonstrated that combined targeting of XPO1 and ERα rewired the metabolic pathways and shut down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies to improve therapy response in relapsed ERα (+) tumors, our findings show great promise for uncovering the role that ERα-XPO1 crosstalk plays in reducing cancer recurrences.
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http://dx.doi.org/10.3390/cancers11040479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520695PMC
April 2019
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