Publications by authors named "Sharon Lin"

49 Publications

Specialist respiratory outreach: a case-finding initiative for identifying undiagnosed COPD in primary care.

NPJ Prim Care Respir Med 2021 02 11;31(1). Epub 2021 Feb 11.

Faculty of Medicine, University of Southampton, Southampton, UK.

COPD remains largely undiagnosed or is diagnosed late in the course of disease. We report findings of a specialist outreach programme to identify undiagnosed COPD in primary care. An electronic case-finding algorithm identified 1602 at-risk patients from 12 practices who were invited to attend the clinic. Three hundred and eighty-three (23.9%) responded and 288 were enrolled into the study. Forty-eight (16.6%) had undiagnosed mild and 28 (9.7%) had moderate airway obstruction, meeting spirometric diagnostic criteria for COPD. However, at 12 months only 8 suspected COPD patients (10.6%) had received a diagnostic label in their primary care record. This constituted 0.38% of the total patient population, as compared with 0.31% of control practices, p = 0.306. However, if all patients with airway obstruction received a coding of COPD, then the diagnosis rate in the intervention group would have risen by 0.84%. Despite the low take-up and diagnostic yield, this programme suggests that integrated case-finding strategies could improve COPD recognition.
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http://dx.doi.org/10.1038/s41533-021-00219-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878732PMC
February 2021

Leveraging Free Volume Manipulation to Improve the Membrane Separation Performance of Amine-Functionalized PIM-1.

Angew Chem Int Ed Engl 2021 Mar 12;60(12):6593-6599. Epub 2021 Feb 12.

Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA, 02139, USA.

Gas-separation polymer membranes display a characteristic permeability-selectivity trade-off that has limited their industrial use. The most comprehensive approach to improving performance is to devise strategies that simultaneously increase fractional free volume, narrow free volume distribution, and enhance sorption selectivity, but generalizable methods for such approaches are exceedingly rare. Here, we present an in situ crosslinking and solid-state deprotection method to access previously inaccessible sorption and diffusion characteristics in amine-functionalized polymers of intrinsic microporosity. Free volume element (FVE) size can be increased while preserving a narrow FVE distribution, enabling below-upper bound polymers to surpass the H /N , H /CH , and O /N upper bounds and improving CO -based selectivities by 200 %. This approach can transform polymers into chemical analogues with improved performance, thereby overcoming traditional permeability-selectivity trade-offs.
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http://dx.doi.org/10.1002/anie.202012441DOI Listing
March 2021

Cervical Fibrosis as a Predictor of Dysphagia.

Laryngoscope 2021 03 6;131(3):548-552. Epub 2020 Jul 6.

Department of Otolaryngology-Head and Neck Surgery, University of California Davis, Sacramento, California, U.S.A.

Objective: Radiotherapy of head and neck cancer (HNCA) causes dysfunction through radiation-induced fibrosis (RIF). We hypothesize that the degree of cervical fibrosis is associated with swallowing dysfunction. This study evaluated the association between cervical fibrosis and swallowing dysfunction in patients after radiation therapy for HNCA.

Study Design: Cross sectional study.

Methodology: A convenience sample of patients with dysphagia who were at least 1 year post radiation therapy for HNCA underwent simultaneous cervical ultrasound (US) and video-fluroscopic swallow study (VFSS). US determinants of fibrosis were measurements of sternocleidomastoid fascia (SCMF) thickness bilaterally at the level of the cricoid. Primary and secondary outcome variables on VFSS were pharyngeal constriction ratio, a validated measure of pharyngeal contractility, and penetration aspiration scale (PAS). A qualitative assessment of lateral neck rotation was performed as a functional measure of neck fibrosis.

Results: Simultaneous cervical US and VFSS examinations were performed on 18 patients with a history of radiotherapy for HNCA and on eight controls. The mean (±SD) age of the entire cohort (N = 26) was 66 (±10) years. Individuals with a history of radiation had significantly thinner mean SCMF (0.26 [±0.04 mm]) compared to controls (0.48 [±0.06 mm]; P < .05). Individuals with thinner SCMF were more likely to have moderate to severe restriction in lateral neck rotation, a higher PCR, and a higher PAS (P < .05).

Conclusion: Thinner sternocleidomastoid fascia on ultrasound in patients having undergone radiotherapy for head and neck cancer was associated with reduced lateral neck movement, poorer pharyngeal constriction and greater penetration/aspiration scale. The data suggest that cervical fibrosis is associated with swallowing dysfunction in head and neck cancer survivors and support the notion that, "As the neck goes, so does the swallow."

Level Of Evidence: 3. Laryngoscope, 131:548-552, 2021.
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http://dx.doi.org/10.1002/lary.28880DOI Listing
March 2021

MOF-Based Membranes for Gas Separations.

Chem Rev 2020 Aug 1;120(16):8161-8266. Epub 2020 Jul 1.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

Metal-organic frameworks (MOFs) represent the largest known class of porous crystalline materials ever synthesized. Their narrow pore windows and nearly unlimited structural and chemical features have made these materials of significant interest for membrane-based gas separations. In this comprehensive review, we discuss opportunities and challenges related to the formation of pure MOF films and mixed-matrix membranes (MMMs). Common and emerging separation applications are identified, and membrane transport theory for MOFs is described and contextualized relative to the governing principles that describe transport in polymers. Additionally, cross-cutting research opportunities using advanced metrologies and computational techniques are reviewed. To quantify membrane performance, we introduce a simple membrane performance score that has been tabulated for all of the literature data compiled in this review. These data are reported on upper bound plots, revealing classes of MOF materials that consistently demonstrate promising separation performance. Recommendations are provided with the intent of identifying the most promising materials and directions for the field in terms of fundamental science and eventual deployment of MOF materials for commercial membrane-based gas separations.
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http://dx.doi.org/10.1021/acs.chemrev.0c00119DOI Listing
August 2020

Findings from a pilot randomised trial of a social network self-management intervention in COPD.

BMC Pulm Med 2020 Jun 8;20(1):162. Epub 2020 Jun 8.

NIHR Wessex CLARHC, Southampton, UK.

Background: Self-Management Support (SMS), refers to the actions taken by individuals to recognise and manage their own health. It is increasingly recognised that individuals with chronic obstructive pulmonary disease (COPD) require additional support with their Self-management. Emerging evidence suggests that the use of a social network intervention can improve health outcomes and increase quality of life. In order to understand the potential benefits of SMS in COPD, the GENIE (Generating Engagement in Network Support) SMS tool was implemented and evaluated in a COPD primary care context. The GENIE intervention is a social networking tool that consists of 3 parts; a concentric circle modelling to map existing social networks; a questions sections to elicit preferences for activities; a map of selected resources is then produced, aligned with the user's interests and suggestions for connections to existing network members and to new resources.

Methods: A pilot, parallel, single blind, block randomised controlled trial. Patients with COPD ranging from mild-very severe were recruited. Participants provided written consent and were then randomised to either the intervention or usual care. The primary aim was to understand the clinical benefit through the analysis of health status, symptom burden and quality of life. The secondary outcome measure was health utilisation. NHS cost differences were reported between groups using the GENIE intervention over usual care.

Results: The GENIE pilot results demonstrate maintenance in health status and clinical symptoms with a decrease in anxiety. An overall increase in quality of life was observed, these findings did not reach significance. A cost reduction was demonstrated in inpatient stay with no difference in primary care costs. Overall a cost reduction in NHS service utilisation was indicated in the intervention group.

Conclusion: This pilot study indicated that using a social network intervention can encourage the development of new social connections and extend existing support networks for COPD patients. Increasing network support in this population is of benefit to both patients and NHS providers in terms of cost reductions and enhancing wellbeing. This broadens the understanding of possible new approaches to SMS in community COPD patients, which could now be investigated in a larger population over a longer period.

Trial Registration: Clinical Trials.gov PRS National Library of Medicine. Protocol ID number: 19175, Clinical Trial ID: NCT02935452.
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http://dx.doi.org/10.1186/s12890-020-1130-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278059PMC
June 2020

Multi-Institutional Regional Otolaryngology Bootcamp.

Ann Otol Rhinol Laryngol 2020 Jun 29;129(6):605-610. Epub 2020 Jan 29.

Department of Otolaryngology, Division of Head and Neck Surgery, University of California, Davis, Sacramento, CA, USA.

Introduction: In order to increase junior resident physician proficiency and improve patient safety, simulation-based procedural training courses, or bootcamps, have been become an emerging educational tool.

Objectives: To compare pre- and post-course confidence levels and to assess station efficacy after completion of our single day bootcamp.

Methods: We developed the University of California (UC) Davis otolaryngology bootcamp, a single day course including six cadaveric task trainer stations and four simulations. The six task trainer stations included (1) Epistaxis, (2) Cricothyrotomy/tracheostomy, (3) Peritonsillar abscess/auricular hematoma, (4) Nasal bone reduction/zygoma reduction/lateral canthotomy/canalicular trauma and probing, (5) Local nerve blocks, and (6) Soft tissue reconstruction. The simulations comprised of airway fire during tracheostomy, pediatric respiratory code during airway evaluation, dislodged pediatric tracheostomy tube in the ICU, and angioedema in the emergency department with inability to intubate or ventilate. Junior residents from multiple locoregional institutions were recruited to participate. Pre- and post-course Likert surveys assessing participant confidence and station efficacy were collected and analyzed.

Results: There was a statistically significant increase in resident confidence levels for all task trainer stations. All stations had a station efficacy Likert score average of 4 "very effective" or 5 "most effective."

Conclusion: A multi-institutional, locoregional, simulation-based bootcamp can be a valuable adjunct to junior resident training. It can promote camaraderie, pool limited resources, and may be cost-effective.
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http://dx.doi.org/10.1177/0003489420903067DOI Listing
June 2020

An Economic Model of Optimal Penalty for Health Care Workplace Violence.

Inquiry 2019 Jan-Dec;56:46958019884190

Tongde Hospital of Zhejiang Province, Hangzhou, China.

This article provides an economic model on the optimal penalty of health care workplace violence based on health care workplace classification and cost structure, aiming to deter potential offenders. By developing an EIP (externality, identifiability, and preventability) analytical method, we distinguish the characteristics of different workplaces and find that the health care workplace is the combination of externality, low identifiability, and low preventability. Besides the private cost to victims for ordinary workplace violence, the cost structure of health care workplace violence includes social costs like externality-related public safety cost, defensive medicine cost, and specific factors cost. When the optimal penalty corresponding to different levels of health care workplace violence increases, the threshold level of punishable violence decreases after incorporating the social costs into analysis. Our model shows that public safety costs are positively correlated with the importance of health care workplace in the service network, and a higher public safety cost should be matched with a greater optimal penalty.
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http://dx.doi.org/10.1177/0046958019884190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811755PMC
February 2020

Mixed-Matrix Membranes Formed from Imide-Functionalized UiO-66-NH for Improved Interfacial Compatibility.

ACS Appl Mater Interfaces 2019 Aug 14;11(34):31257-31269. Epub 2019 Aug 14.

Department of Chemical Engineering , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.

Mixed-matrix membranes (MMMs) formed by dispersing metal-organic framework (MOF) particles in polymers have attracted significant attention because these composite systems can potentially surpass the separation performance of pure polymers alone. However, performance improvements are often unrealized because of poor interfacial compatibility between the MOF and the polymer, which results in interfacial defects. From a practical perspective, strategies are needed to address these defects so that MMMs can be deployed in real-world separation processes. From a fundamental perspective, strategies are needed to reliably form defect-free MMMs so that transport models can be applied to estimate pure MOF property sets, thereby enabling the development of robust structure-property relationships. To address these interfacial challenges, we have developed a method to surface-functionalize a UiO-66-NH MOF with a nanoscopic shell of covalently tethered 4,4'-(hexafluoroisopropylidene)diphthalic anhydride-Durene oligomers. When combined with a high-molecular-weight polymer of identical chemical structure to that of the imide-functional MOF surface, defect-free MMMs with uniform particle dispersions can be formed. With this technique, both permeabilities and selectivities of select gases in the MMMs were improved at loadings ranging from 5 to 40 wt %. At a 40 wt % loading, CO permeability and CO/CH selectivity were enhanced by 48 and 15%, respectively. Additionally, pure MOF permeabilities for H, N, O, CH, and CO were predicted by the Maxwell model.
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http://dx.doi.org/10.1021/acsami.9b07500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727620PMC
August 2019

Eustachian tube dysfunction in children with cleft palate: A tympanometric time-to-event analysis.

Laryngoscope 2020 04 13;130(4):1044-1050. Epub 2019 Jun 13.

Department of Otolaryngology-Head & Neck Surgery, UC Davis Health, Sacramento, California, U.S.A.

Objectives: To characterize the duration of Eustachian tube dysfunction in children with cleft palate compared to those without cleft palate by performing time-to-event analysis on tympanometric data. To determine predictive characteristics of earlier achievement of normal tympanograms in children with cleft palate.

Methods: Longitudinal tympanometric data from a minimum of 10 years at a single center were reviewed for children with cleft palate born in the years 2003 through 2007. Children with cleft lip without cleft palate born in the same years were used as a reference group to compare children with similar length of follow-up. The association between time to sustained normal (type A) tympanograms with patient demographics, clinical characteristics, and otologic history was evaluated using time-to-event analysis and compared with log rank tests. Adjusted and unadjusted hazard ratios were estimated using Cox proportional hazard models.

Results: The median age of achieving a type A tympanogram in children with cleft palate was 9.9 years for one and 12.1 years for both ears, compared to 7.1 and 7.4 years in children with cleft lip only (P < 0.0001). On multivariate analysis, clinical characteristics such as the severity of palatal clefting or the presence of a cleft-associated syndrome/sequence were not predictors of a longer time to a type A tympanogram.

Conclusion: Our results help characterize the observation that there is delayed time to normal Eustachian tube function in children with cleft palate, which is not associated with the degree of palatal clefting.

Level Of Evidence: 3b Laryngoscope, 130:1044-1050, 2020.
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http://dx.doi.org/10.1002/lary.28103DOI Listing
April 2020

Polymers with Side Chain Porosity for Ultrapermeable and Plasticization Resistant Materials for Gas Separations.

Adv Mater 2019 May 9;31(21):e1807871. Epub 2019 Apr 9.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Polymer membranes with ultrahigh CO permeabilities and high selectivities are needed to address some of the critical separation challenges related to energy and the environment, especially in natural gas purification and postcombustion carbon capture. However, very few solution-processable, linear polymers are known today that access these types of characteristics, and all of the known structures achieve their separation performance through the design of rigid backbone chemistries that concomitantly increase chain stiffness and interchain spacing, thereby resulting in ultramicroporosity in solid-state chain-entangled films. Herein, the separation performance of a porous polymer obtained via ring-opening metathesis polymerization is reported, which possesses a flexible backbone with rigid, fluorinated side chains. This polymer exhibits ultrahigh CO permeability (>21 000 Barrer) and exceptional plasticization resistance (CO plasticization pressure > 51 bar). Compared to traditional polymers of intrinsic microporosity, the rate of physical aging is slower, especially for gases with small effective diameters (i.e., He, H , and O ). This structural design strategy, coupled with studies on fluorination, demonstrates a generalizable approach to create new polymers with flexible backbones and pore-forming side chains that have unexplored promise for small-molecule separations.
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http://dx.doi.org/10.1002/adma.201807871DOI Listing
May 2019

Can trained volunteers improve the mealtime care of older hospital patients? An implementation study in one English hospital.

BMJ Open 2018 08 5;8(8):e022285. Epub 2018 Aug 5.

Medicine for Older People, University Hospital Southampton NHS FT, Southampton General Hospital, Southampton, UK.

Objective: Multinational studies report undernutrition among 39% older inpatients; importantly, malnutrition risk may further increase while in hospital. Contributory factors include insufficient mealtime assistance from time-pressured hospital staff. A pilot study showed trained volunteers could safely improve mealtime care. This study evaluates the wider implementation of a mealtime assistance programme.

Design: Mixed methods prospective quasi-experimental study.

Setting: Nine wards across Medicine for Older People (MOP), Acute Medical Unit, Orthopaedics and Adult Medicine departments in one English hospital.

Participants: Patients, volunteers, ward staff.

Intervention: Volunteers trained to help patients aged ≥70 years at weekday lunchtime and evening meals.

Main Outcome Measures: The number of volunteers recruited, trained and their activity was recorded. Barriers and enablers to the intervention were explored through interviews and focus groups with patients, ward staff and volunteers. The total cost of the programme was evaluated.

Results: 65 volunteers (52 female) helped at 846 meals (median eight/volunteer, range 2-109). The mix of ages (17-77 years) and employment status enabled lunch and evening mealtimes to be covered. Feeding patients was the most common activity volunteers performed, comprising 56% of volunteer interactions on MOP and 34%-35% in other departments. Patients and nurses universally valued the volunteers, who were skilled at encouraging reluctant eaters. Training was seen as essential by volunteers, patients and staff. The volunteers released potential costs of clinical time equivalent to a saving of £27.04/patient/day of healthcare assistant time or £45.04 of newly qualified nurse time above their training costs during the study.

Conclusions: Patients in all departments had a high level of need for mealtime assistance. Trained volunteers were highly valued by patients and staff. The programme was cost-saving releasing valuable nursing time.

Trial Registration Number: NCT02229019; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078263PMC
August 2018

The contribution of internet use in personal networks of support for long-term condition self-management.

Chronic Illn 2019 09 28;15(3):220-235. Epub 2018 Feb 28.

NIHR CLAHRC Wessex, School of Health Sciences, University of Southampton, UK.

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http://dx.doi.org/10.1177/1742395318759588DOI Listing
September 2019

Post-operative MRSA infections in head and neck surgery.

Am J Otolaryngol 2017 Jul - Aug;38(4):417-421. Epub 2017 Mar 31.

Ear, Nose, and Throat Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, United States. Electronic address:

Purpose: Surgical site infection (SSI) with methicillin-resistant Staphylococcus aureus (MRSA) is a serious post-operative complication, with head and neck cancer patients at greater risk due to the nature of their disease. Infection with MRSA has been shown to be costly and impart worse outcomes on patients who are affected. This study investigates incidence and risks for MRSA SSIs at a tertiary medical institution.

Materials And Methods: This study reviewed 577 head and neck procedures from 2008 to 2013. Twenty-one variables (i.e. tumor characteristics, patient demographics, operative course, cultures) were analyzed with SPSS to identify trends. A multivariate analysis controlled for confounders (age, BMI, ASA class, length of stay) was completed.

Results: We identified 113 SSIs of 577 procedures, 24 (21.23%) of which were MRSA. Of all analyzed variables, hospital exposure within the preceding year was a significant risk factor for MRSA SSI development (OR 2.665, 95% CI: 1.06-6.69, z statistic 2.086, p=0.0369). Immunosuppressed patients were more prone to MRSA infections (OR 14.1250, 95%CI: 3.8133-52.3217, p<0.001), and patients with a history of chemotherapy (OR 3.0268, 95% CI: 1.1750-7.7968, p=0.0218). Furthermore, MRSA SSI resulted in extended post-operative hospital stays (20.8±4.72days, p=0.031).

Conclusions: Patients who have a history of chemotherapy, immunosuppression, or recent hospital exposure prior to their surgery are at higher risk of developing MRSA-specific SSI and may benefit from prophylactic antibiotic therapy with appropriate coverage. Additionally, patients who develop MRSA SSIs are likely to have an extended postoperative inpatient stay.
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http://dx.doi.org/10.1016/j.amjoto.2017.03.013DOI Listing
May 2018

Production and in vitro evaluation of macroporous, cell-encapsulating alginate fibres for nerve repair.

Mater Sci Eng C Mater Biol Appl 2017 Apr 14;73:653-664. Epub 2016 Dec 14.

Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand. Electronic address:

The prospects for successful peripheral nerve repair using fibre guides are considered to be enhanced by the use of a scaffold material, which promotes attachment and proliferation of glial cells and axonal regeneration. Macroporous alginate fibres were produced by extraction of gelatin particle porogens from wet spun fibres produced using a suspension of gelatin particles in 1.5% w/v alginate solution. Gelatin loading of the starting suspension of 40.0, 57.0, and 62.5% w/w resulted in gelatin loading of the dried alginate fibres of 16, 21, and 24% w/w respectively. Between 45 and 60% of the gelatin content of hydrated fibres was released in 1h in distilled water at 37°C, leading to rapid formation of a macroporous structure. Confocal laser scanning microscopy (CLSM) and image processing provided qualitative and quantitative analysis of mean equivalent macropore diameter (48-69μm), pore size distribution, estimates of maximum porosity (14.6%) and pore connectivity. CLSM also revealed that gelatin residues lined the macropore cavities and infiltrated into the body of the alginate scaffolds, thus, providing cell adhesion molecules, which are potentially advantageous for promoting growth of glial cells and axonal extension. Macroporous alginate fibres encapsulating nerve cells [primary rat dorsal root ganglia (DRGs)] were produced by wet spinning alginate solution containing dispersed gelatin particles and DRGs. Marked outgrowth was evident over a distance of 150μm at day 11 in cell culture, indicating that pores and channels created within the alginate hydrogel were providing a favourable environment for neurite development. These findings indicate that macroporous alginate fibres encapsulating nerve cells may provide the basis of a useful strategy for nerve repair.
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http://dx.doi.org/10.1016/j.msec.2016.12.016DOI Listing
April 2017

Treatment of ear and bone disease in the Phex mouse mutant with dietary supplementation.

Am J Otolaryngol 2017 Jan - Feb;38(1):44-51. Epub 2016 Sep 28.

Ear, Nose, and Throat Institute, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, U.S.A.

Hypothesis: Phosphorus and vitamin D (calcitriol) supplementation in the Phex mouse, a murine model for endolymphatic hydrops (ELH), will improve otic capsule mineralization and secondarily ameliorate the postnatal development of ELH and sensorineural hearing loss (SNHL).

Background: Male Phex mice have X-linked hypophosphatemic rickets (XLH), which includes osteomalacia of the otic capsule. The treatment for XLH is supplementation with phosphorus and calcitriol. The effect of this treatment has never been studied on otic capsule bone and it is unclear if improving the otic capsule bone could impact the mice's postnatal development of ELH and SNHL.

Methods: Four cohorts were studied: 1) wild-type control, 2) Phex control, 3) Phex prevention, and 4) Phex rescue. The control groups were not given any dietary supplementation. The Phex prevention group was supplemented with phosphorus added to its drinking water and intraperitoneal calcitriol from postnatal day (P) 7-P40. The Phex rescue group was also supplemented with phosphorus and calcium but only from P20 to P40. At P40, all mice underwent auditory brainstem response (ABR) testing, serum analysis, and temporal bone histologic analysis. Primary outcome was otic capsule mineralization. Secondary outcomes were degree of SNHL and presence ELH.

Results: Both treatment groups had markedly improved otic capsule mineralization with less osteoid deposition. The improved otic capsule mineralized did not prevent the development of ELH or SNHL.

Conclusion: Supplementation with phosphorus and calcitriol improves otic capsule bone morphology in the Phex male mouse but does not alter development of ELH or SNHL.
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http://dx.doi.org/10.1016/j.amjoto.2016.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221453PMC
October 2017

Gold Nanoantenna-Mediated Photothermal Drug Delivery from Thermosensitive Liposomes in Breast Cancer.

ACS Omega 2016 Aug 24;1(2):234-243. Epub 2016 Aug 24.

Department of Chemical and Biomolecular Engineering, Department of Mechanical Engineering, Department of Biomedical Engineering, and Vanderbilt Center for Immunobiology, Vanderbilt University , 2301 Vanderbilt Place, Nashville, TN 37215, United States.

In this work, we demonstrate controlled drug delivery from low-temperature-sensitive liposomes (LTSLs) mediated by photothermal heating from multibranched gold nanoantennas (MGNs) in triple-negative breast cancer (TNBC) cells in vitro. The unique geometry of MGNs enables the generation of mild hyperthermia (∼42 °C) by converting near-infrared light to heat and effectively delivering doxorubicin (DOX) from the LTSLs in breast cancer cells. We confirmed the cellular uptake of MGNs by using both fluorescence confocal Z-stack imaging and transmission electron microscopy (TEM) imaging. We performed a cellular viability assay and live/dead cell fluorescence imaging of the combined therapeutic effects of MGNs with DOX-loaded LTSLs (DOX-LTSLs) and compared them with free DOX and DOX-loaded non-temperature-sensitive liposomes (DOX-NTSLs). Imaging of fluorescent live/dead cell indicators and MTT assay outcomes both demonstrated significant decreases in cellular viability when cells were treated with the combination therapy. Because of the high phase-transition temperature of NTSLs, no drug delivery was observed from the DOX-NTSLs. Notably, even at a low DOX concentration of 0.5 μg/mL, the combination treatment resulted in a higher (33%) cell death relative to free DOX (17% cell death). The results of our work demonstrate that the synergistic therapeutic effect of photothermal hyperthermia of MGNs with drug delivery from the LTSLs can successfully eradicate aggressive breast cancer cells with higher efficacy than free DOX by providing a controlled light-activated approach and minimizing off-target toxicity.
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http://dx.doi.org/10.1021/acsomega.6b00079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026460PMC
August 2016

Properties of bootstrap tests for N-of-1 studies.

Br J Math Stat Psychol 2016 Nov;69(3):276-290

Academic Unit of Psychology, University of Southampton, UK.

N-of-1 study designs involve the collection and analysis of repeated measures data from an individual not using an intervention and using an intervention. This study explores the use of semi-parametric and parametric bootstrap tests in the analysis of N-of-1 studies under a single time series framework in the presence of autocorrelation. When the Type I error rates of bootstrap tests are compared to Wald tests, our results show that the bootstrap tests have more desirable properties. We compare the results for normally distributed errors with those for contaminated normally distributed errors and find that, except when there is relatively large autocorrelation, there is little difference between the power of the parametric and semi-parametric bootstrap tests. We also experiment with two intervention designs: ABAB and AB, and show the ABAB design has more power. The results provide guidelines for designing N-of-1 studies, in the sense of how many observations and how many intervention changes are needed to achieve a certain level of power and which test should be performed.
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http://dx.doi.org/10.1111/bmsp.12071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082548PMC
November 2016

Structure-Function Assessment of Mannosylated Poly(β-amino esters) upon Targeted Antigen Presenting Cell Gene Delivery.

Biomacromolecules 2015 May 16;16(5):1534-41. Epub 2015 Apr 16.

Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, New York, United States.

Antigen presenting cell (APC) gene delivery is a promising avenue for modulating immunological outcomes toward a desired state. Recently, our group developed a delivery methodology to elicit targeted and elevated levels of APC-mediated gene delivery. During these initial studies, we observed APC-specific structure-function relationships with the vectors used during gene delivery that differ from current non-APC cell lines, thus, emphasizing a need to re-evaluate vector-associated parameters in the context of APC gene transfer. Thus, we describe the synthesis and characterization of a second-generation mannosylated poly(β-amino ester) library stratified by molecular weight. To better understand the APC-specific structure-function relationships governing polymeric gene delivery, the library was systematically characterized by (1) polymer molecular weight, (2) relative mannose content, (3) polyplex biophysical properties, and (4) gene delivery efficacy. In this library, polymers with the lowest molecular weight and highest relative mannose content possessed gene delivery transfection efficiencies as good as or better than commercial controls. Among this group, the most effective polymers formed the smallest polymer-plasmid DNA complexes (∼300 nm) with moderate charge densities (<10 mV). This convergence in polymer structure and polyplex biophysical properties suggests a unique mode of action and provides a framework within which future APC-targeting polymers can be designed.
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http://dx.doi.org/10.1021/acs.biomac.5b00062DOI Listing
May 2015

RNAa in action: from the exception to the norm.

RNA Biol 2014 ;11(10):1221-5

a Laboratory of Molecular Medicine; Peking Union Medical College Hospital; Chinese Academy of Medical Sciences and Peking Union Medical College ; Beijing , China.

Small RNA programmed Argonautes are sophisticated cellular effector platforms known to be involved in a diverse array of functions ranging from mRNA cleavage, translational inhibition, DNA elimination, epigenetic silencing, alternative splicing and even gene activation. First observed in human cells, small RNA-induced gene activation, also known as RNAa, involves the targeted recruitment of Argonaute proteins to specific promoter sequences followed by induction of stable epigenetic changes which promote transcription. The existence of RNAa remains contentious due to its elusive mechanism. A string of recent studies in C. elegans provides unequivocal evidence for RNAa's fundamental role in sculpting the epigenetic landscape and maintaining active transcription of endogenous genes and supports the presence of a functionally sophisticated network of small RNA-Argonaute pathways consisting of opposite yet complementary "yin and yang" regulatory elements. In this review, we summarize key findings from recent studies of endogenous RNAa in C. elegans, with an emphasis on the Argonaute protein CSR-1.
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http://dx.doi.org/10.4161/15476286.2014.972853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615537PMC
September 2015

Understanding usage of a hybrid website and smartphone app for weight management: a mixed-methods study.

J Med Internet Res 2014 Oct 22;16(10):e201. Epub 2014 Oct 22.

Centre for Applications of Health Psychology, Academic Unit of Psychology, University of Southampton, Southampton, United Kingdom.

Background: Advancements in mobile phone technology offer huge potential for enhancing the timely delivery of health behavior change interventions. The development of smartphone-based health interventions (apps) is a rapidly growing field of research, yet there have been few longitudinal examinations of how people experience and use these apps within their day-to-day routines, particularly within the context of a hybrid Web- and app-based intervention.

Objective: This study used an in-depth mixed-methods design to examine individual variation in (1) impact on self-reported goal engagement (ie, motivation, self-efficacy, awareness, effort, achievement) of access to a weight management app (POWeR Tracker) when provided alongside a Web-based weight management intervention (POWeR) and (2) usage and views of POWeR Tracker.

Methods: Thirteen adults were provided access to POWeR and were monitored over a 4-week period. Access to POWeR Tracker was provided in 2 alternate weeks (ie, weeks 1 and 3 or weeks 2 and 4). Participants' goal engagement was measured daily via self-report. Mixed effects models were used to examine change in goal engagement between the weeks when POWeR Tracker was and was not available and whether the extent of change in goal engagement varied between individual participants. Usage of POWeR and POWeR Tracker was automatically recorded for each participant. Telephone interviews were conducted and analyzed using inductive thematic analysis to further explore participants' experiences using POWeR and POWeR Tracker.

Results: Access to POWeR Tracker was associated with a significant increase in participants' awareness of their eating (β1=0.31, P=.04) and physical activity goals (β1=0.28, P=.03). The level of increase varied between individual participants. Usage data showed that participants used the POWeR website for similar amounts of time during the weeks when POWeR Tracker was (mean 29 minutes, SD 31 minutes) and was not available (mean 27 minutes, SD 33 minutes). POWeR Tracker was mostly accessed in short bursts (mean 3 minutes, SD 2 minutes) during convenient moments or moments when participants deemed the intervention content most relevant. The qualitative data indicated that nearly all participants agreed that it was more convenient to access information on-the-go via their mobiles compared to a computer. However, participants varied in their views and usage of the Web- versus app-based components and the informational versus tracking tools provided by POWeR Tracker.

Conclusions: This study provides evidence that smartphones have the potential to improve individuals' engagement with their health-related goals when used as a supplement to an existing online intervention. The perceived convenience of mobile access to information does not appear to deter use of Web-based interventions or strengthen the impact of app access on goal engagement. A mixed-methods design enabled exploration of individual variation in daily usage of the app-based tools.
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http://dx.doi.org/10.2196/jmir.3579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259922PMC
October 2014

Deletion of Mecom in mouse results in early-onset spinal deformity and osteopenia.

Bone 2014 Mar 4;60:148-61. Epub 2013 Dec 4.

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, USA. Electronic address:

Recent studies have indicated a role for a MECOM allele in susceptibility to osteoporotic fractures in humans. We have generated a mutation in Mecom in mouse (termed ME(m1)) via lacZ knock-in into the upstream transcription start site for the gene, resulting in disruption of Mds1 and Mds1-Evi1 transcripts, but not of Evi1 transcripts. We demonstrate that ME(m1/m1) mice have severe kyphoscoliosis that is reminiscent of human congenital or primary kyphoscoliosis. ME(m1/m1) mice appear normal at birth, but by 2weeks, they exhibit a slight lumbar lordosis and narrowed intervertebral space. This progresses to severe lordosis with disc collapse and synostosis, together with kyphoscoliosis. Bone formation and strength testing show that ME(m1/m1) mice have normal bone formation and composition but are osteopenic. While endochondral bone development is normal, it is markedly dysplastic in its organization. Electron micrographs of the 1week postnatal intervertebral discs reveals marked disarray of collagen fibers, consistent with an inherent weakness in the non-osseous connective tissue associated with the spine. These findings indicate that lack of ME leads to a complex defect in both osseous and non-osseous musculoskeletal tissues, including a marked vertebral osteopenia, degeneration of the IVD, and disarray of connective tissues, which is likely due to an inherent inability to establish and/or maintain components of these tissues.
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http://dx.doi.org/10.1016/j.bone.2013.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440591PMC
March 2014

Nuclear monomeric integrin αv in cancer cells is a coactivator regulated by thyroid hormone.

FASEB J 2013 Aug 2;27(8):3209-16. Epub 2013 May 2.

Institute of Cancer Biology and Drug Discovery, Taipei Medical University, 250 Wu-Shin St., Taipei, Taiwan.

Thyroid hormone induces tumor cell and blood vessel cell proliferation via a cell surface receptor on heterodimeric integrin αvβ3. We investigated the role of thyroid hormone-induced internalization of nuclear integrin αv monomer. Physiological concentration of thyroxine (free T4, 10(-10) M), but not 3,5,3'-triiodo-l-thyronine (T3), induced cellular internalization and nuclear translocation of integrin αv monomer in human non-small-cell lung cancer (H522) and ovarian carcinoma (OVCAR-3) cells. T4 did not complex with integrin αv monomer during its internalization. The αv monomer was phosphorylated by activated ERK1/2 when it heterodimerized with integrin β3 in vitro. Nuclear αv complexed with transcriptional coactivator proteins, p300 and STAT1, and with corepressor proteins, NCoR and SMRT. Nuclear αv monomer in T4-exposed cells, but not integrin β3, bound to promoters of specific genes that have important roles in cancer cells, including estrogen receptor-α, cyclooxygenase-2, hypoxia-inducible factor-1α, and thyroid hormone receptor β1 in chromatin immunoprecipitation assay. In summary, monomeric αv is a novel coactivator regulated from the cell surface by thyroid hormone for the expression of genes involved in tumorigenesis and angiogenesis. This study also offers a mechanism for modulation of gene expression by thyroid hormone that is adjunctive to the nuclear hormone receptor (TR)-T3 pathway.
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http://dx.doi.org/10.1096/fj.12-227132DOI Listing
August 2013

Age increase of estrogen receptor-α (ERα) in cortical astrocytes impairs neurotrophic support in male and female rats.

Endocrinology 2013 Jun 20;154(6):2101-13. Epub 2013 Mar 20.

Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089-0191, USA.

Rodent models show decreased neuronal responses to estradiol (E2) during aging (E2-desensitization) in association with reduced neuronal estrogen receptor (ER)-α, but little is known about age changes of E2-dependent astrocytic neurotrophic support. Because elevated expression of astrocyte glial fibrillary acidic protein (GFAP) is associated with impaired neurotrophic activity and because the GFAP promoter responds to ERα, we investigated the role of astrocytic ERα and ERβ in impaired astrocyte neurotrophic activity during aging. In vivo and in vitro, ERα was increased greater than 50% with age in astrocytes from the cerebral cortex of male rats (24 vs 3 months), whereas ERβ did not change. In astrocytes from 3-month-old males, experimentally increasing the ERα to ERβ ratio induced the aging phenotype of elevated GFAP and impaired E2-dependent neurite outgrowth. In 24-month-old male astrocytes, lowering ERα reversed the age elevation of GFAP and partially restored E2-dependent neurite outgrowth. Mixed glia (astrocytes to microglia, 3:1) of both sexes also showed these age changes. In a model of perimenopause, mixed glia from 9- to 15-month rats showed E2 desensitization: 9-month regular cyclers retained young-like ERα to ERβ ratios and neurotrophic activity, whereas 9-month noncyclers had elevated ERα and GFAP but low E2-dependent neurotrophic activity. In vivo, ERα levels in cortical astrocytes were also elevated. The persisting effects of ovarian acyclicity in vitro are hypothesized to arise from steroidal perturbations during ovarian senescence. These findings suggest that increased astrocyte ERα expression during aging contributes to the E2 desensitization of the neuronal responses in both sexes.
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http://dx.doi.org/10.1210/en.2012-2046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740484PMC
June 2013

Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol.

J Cell Biochem 2013 Aug;114(8):1940-54

Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.

Ceramide is a member of the sphingolipid family of bioactive molecules demonstrated to have profound, diverse biological activities. Ceramide is a potential chemotherapeutic agent via the induction of apoptosis. Exposure to ceramide activates extracellular-signal-regulated kinases (ERK)1/2- and p38 kinase-dependent apoptosis in human ovarian cancer OVCAR-3 cells, concomitant with an increase in the expression of COX-2 and p53 phosphorylation. Blockade of cyclooxygenase-2 (COX-2) activity by siRNA or NS398 correspondingly inhibited ceramide-induced p53 Ser-15 phosphorylation and apoptosis; thus COX-2 appears at the apex of the p38 kinase-mediated signaling cascade induced by ceramide. Induction of apoptosis by ceramide or resveratrol was inhibited by the endocytosis inhibitor, cytochalasin D (CytD); however, cells exposed to resveratrol showed greater sensitivity than ceramide-treated cells. Ceramide-treated cells underwent a dose-dependent reduction in trans-membrane potential. Although both ceramide and resveratrol induced the expressions of caspase-3 and -7, the effect of inducible COX-2 was different in caspase-7 expression induced by ceramide compared to resveratrol. In summary, resveratrol and ceramide converge on an endocytosis-requiring, ERK1/2-dependent signal transduction pathway and induction of COX-expression as an essential molecular antecedent for subsequent p53-dependent apoptosis. In addition, expressions of caspase-3 and -7 are observed. However, a p38 kinase-dependent signal transduction pathway and change in mitochondrial potential are also involved in ceramide-induced apoptosis.
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http://dx.doi.org/10.1002/jcb.24539DOI Listing
August 2013

Operant psychostimulant self-administration in a rat model of depression.

Pharmacol Biochem Behav 2012 Dec 23;103(2):380-5. Epub 2012 Sep 23.

Department of Human Genetics, Emory University School of Medicine, Whitehead 301, 615 Michael St., Atlanta, GA 30322, USA.

Depression and psychostimulant addiction are co-morbid conditions; depression is a significant risk factor for psychostimulant abuse, and the rate of depression in drug addicts is higher than in the general population. Despite the prevalence of this comorbidity, there are few animal models examining psychostimulant abuse behaviors in depression. We have shown previously that while rats selectively bred for depression-like phenotypes (SwLo) have blunted mesolimbic dopamine (DA) signaling and locomotor responses to dopaminergic drugs, they voluntarily administer excessive amounts of psychostimulants compared to normal or depression-resistant (SwHi) rats in oral consumption paradigms. To determine whether this increased drug intake by depression-sensitive rats extends to operant self-administration, we assessed fixed ratio-1, progressive ratio, extinction, and reinstatement responding for cocaine and amphetamine in SwLo and SwHi rats. Contrary to the oral consumption results, we found that the SwHi rats generally responded more for both cocaine and amphetamine than the SwLo rats in several instances, most notably in the progressive ratio and reinstatement tests. Food-primed reinstatement of food seeking was also elevated in SwHi rats. These results provide further insight into the neurobiology of depression and addiction comorbidity and caution that oral and operant psychostimulant self-administration paradigms can yield different, and this case, opposite results.
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http://dx.doi.org/10.1016/j.pbb.2012.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494799PMC
December 2012

17β-estradiol and progesterone regulate expression of β-amyloid clearance factors in primary neuron cultures and female rat brain.

Endocrinology 2012 Nov 7;153(11):5467-79. Epub 2012 Sep 7.

Neuroscience Graduate Program, University of Southern California, Los Angeles, California 90089, USA.

The accumulation of β-amyloid protein (Aβ) is a key risk factor in the development of Alzheimer's disease. The ovarian sex steroid hormones 17β-estradiol (E(2)) and progesterone (P(4)) have been shown to regulate Aβ accumulation, although the underlying mechanism(s) remain to be fully elucidated. In this study, we investigate the effects of E(2) and P(4) treatment on the expression levels of Aβ clearance factors including insulin-degrading enzyme, neprilysin, endothelin-converting enzyme 1 and 2, angiotensin-converting enzyme, and transthyretin, both in primary neuron cultures and female rat brains. Our results show that E(2) and P(4) affect the expression levels of several Aβ clearance factors in dose- and time-dependent manners. Most notably, expression of insulin-degrading enzyme is significantly increased by both hormones in cultured neurons and in vivo and is inversely associated with the soluble Aβ levels in vivo. These findings further define sex steroid hormone actions involved in regulation of Aβ, a relationship potentially important to therapeutic approaches aimed at reducing risk of Alzheimer's disease.
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http://dx.doi.org/10.1210/en.2012-1464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473201PMC
November 2012

Seizure susceptibility and epileptogenesis in a rat model of epilepsy and depression co-morbidity.

Neuropsychopharmacology 2012 Dec 8;37(13):2756-63. Epub 2012 Aug 8.

Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.

Although a strong co-morbidity exists clinically between epilepsy and depression, the cause of this co-morbidity remains unknown, and a valid animal model is crucial for the identification of underlying mechanisms and the development of a screening tool for novel therapies. Although some rodent models of epilepsy have been reported to display behaviors relevant to affective disorders, the seizure susceptibility of animals prone to depression-like behavior has not been characterized. Toward this end, we assessed several forms of seizure sensitivity and epileptogenesis in rats selectively bred for vulnerability (Swim Lo-Active; SwLo) or resilience (Swim High-Active; SwHi) to depression-like phenotypes. The SwLo rats exhibit decreased motor activity in a swim test and other depression-like phenotypes, whereas the SwHi rats display increased motor activity in a swim test. SwLo rats exhibited a decreased latency to limbic motor seizures following acute pilocarpine administration in the absence of differences in pilocarpine pharmacokinetics, and also had a decreased threshold to tonic seizures induced by electroshock. Approximately half of the SwLo rats, but none of the SwHi rats, had spontaneous limbic motor seizures 5 weeks following pilocarpine-induced status epilepticus. While the number of stimulations required to achieve full amygdala and hippocampal electrical kindling were similar in the two rat lines, SwLo rats had a lower final hippocampal kindling threshold and more wet dog shakes during both amygdala and hippocampal kindling. Combined, these results indicate that SwLo rats are a model of epilepsy and depression co-morbidity that can be used for investigating underlying neurobiological and genetic mechanisms and screening novel therapeutics.
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http://dx.doi.org/10.1038/npp.2012.141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499730PMC
December 2012

MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation.

Blood 2012 Sep 17;120(11):2317-29. Epub 2012 Jul 17.

Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA.

Serum response factor and its transcriptional cofactor MKL1 are critical for megakaryocyte maturation and platelet formation. We show that MKL2, a homologue of MKL1, is expressed in megakaryocytes and plays a role in megakaryocyte maturation. Using a megakaryocyte-specific Mkl2 knockout (KO) mouse on the conventional Mkl1 KO background to produce double KO (DKO) megakaryocytes and platelets, a critical role for MKL2 is revealed. The decrease in megakaryocyte ploidy and platelet counts of DKO mice is more severe than in Mkl1 KO mice. Platelet dysfunction in DKO mice is revealed by prolonged bleeding times and ineffective platelet activation in vitro in response to adenosine 5'-diphosphate. Electron microscopy and immunofluorescence of DKO megakaryocytes and platelets indicate abnormal cytoskeletal and membrane organization with decreased granule complexity. Surprisingly, the DKO mice have a more extreme thrombocytopenia than mice lacking serum response factor (SRF) expression in the megakaryocyte compartment. Comparison of gene expression reveals approximately 4400 genes whose expression is differentially affected in DKO compared with megakaryocytes deficient in SRF, strongly suggesting that MKL1 and MKL2 have both SRF-dependent and SRF-independent activity in megakaryocytopoiesis.
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http://dx.doi.org/10.1182/blood-2012-04-420828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3447785PMC
September 2012

Continuous versus cyclic progesterone exposure differentially regulates hippocampal gene expression and functional profiles.

PLoS One 2012 29;7(2):e31267. Epub 2012 Feb 29.

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States of America.

This study investigated the impact of chronic exposure to continuous (CoP4) versus cyclic progesterone (CyP4) alone or in combination with 17β-estradiol (E2) on gene expression profiles targeting bioenergetics, metabolism and inflammation in the adult female rat hippocampus. High-throughput qRT-PCR analyses revealed that ovarian hormonal depletion induced by ovariectomy (OVX) led to multiple significant gene expression alterations, which were to a great extent reversed by co-administration of E2 and CyP4. In contrast, co-administration of E2 and CoP4 induced a pattern highly resembling OVX. Bioinformatics analyses further revealed clear disparities in functional profiles associated with E2+CoP4 and E2+CyP4. Genes involved in mitochondrial energy (ATP synthase α subunit; Atp5a1), redox homeostasis (peroxiredoxin 5; Prdx5), insulin signaling (insulin-like growth factor I; Igf1), and cholesterol trafficking (liver X receptor α subtype; Nr1h3), differed in direction of regulation by E2+CoP4 (down-regulation relative to OVX) and E2+CyP4 (up-regulation relative to OVX). In contrast, genes involved in amyloid metabolism (β-secretase; Bace1) differed only in degree of regulation, as both E2+CoP4 and E2+CyP4 induced down-regulation at different efficacy. E2+CyP4-induced changes could be associated with regulation of progesterone receptor membrane component 1(Pgrmc1). In summary, results from this study provide evidence at the molecular level that differing regimens of hormone therapy (HT) can induce disparate gene expression profiles in brain. From a translational perspective, confirmation of these results in a model of natural menopause, would imply that the common regimen of continuous combined HT may have adverse consequences whereas a cyclic combined regimen, which is more physiological, could be an effective strategy to maintain neurological health and function throughout menopausal aging.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031267PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290616PMC
July 2012

Role of RhoA-specific guanine exchange factors in regulation of endomitosis in megakaryocytes.

Dev Cell 2012 Mar 1;22(3):573-84. Epub 2012 Mar 1.

Department of Laboratory Medicine, Yale University, New Haven, CT 06520, USA.

Polyploidization can precede the development of aneuploidy in cancer. Polyploidization in megakaryocytes (Mks), in contrast, is a highly controlled developmental process critical for efficient platelet production via unknown mechanisms. Using primary cells, we demonstrate that the guanine exchange factors GEF-H1 and ECT2, which are often overexpressed in cancer and are essential for RhoA activation during cytokinesis, must be downregulated for Mk polyploidization. The first (2N-4N) endomitotic cycle requires GEF-H1 downregulation, whereas subsequent cycles (>4N) require ECT2 downregulation. Exogenous expression of both GEF-H1 and ECT2 prevents endomitosis, resulting in proliferation of 2N Mks. Furthermore, we have shown that the mechanism by which polyploidization is prevented in Mks lacking Mkl1, which is mutated in megakaryocytic leukemia, is via elevated GEF-H1 expression; shRNA-mediated GEF-H1 knockdown alone rescues this ploidy defect. These mechanistic insights enhance our understanding of normal versus malignant megakaryocytopoiesis, as well as aberrant mitosis in aneuploid cancers.
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http://dx.doi.org/10.1016/j.devcel.2011.12.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306542PMC
March 2012