bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells
Authors: Jackson Mark R. , Bavelaar Bas M. , Waghorn Philip A. , Gill Martin R. , El-Sagheer Afaf H. , Brown Tom , Tarsounas Madalena , Vallis Katherine A. 
Published: July 2019

Abstract

Telomerase is expressed in the majority (&gt;85%) of tumors, but has restricted expression in normal tissues. Long-term telomerase inhibition in malignant cells results in progressive telomere shortening and reduction in cell proliferation. Here we report the synthesis and characterization of radiolabeled oligonucleotides that target the RNA subunit of telomerase, hTR, simultaneously inhibiting enzymatic activity and delivering radiation intracellularly. Oligonucleotides complementary (Match) and noncomplementary (Scramble or Mismatch) to hTR were conjugated to diethylenetriaminepentaacetic dianhydride (DTPA), allowing radiolabeling with the Auger electron-emitting radionuclide indium-111 (111In). Match oligonucleotides inhibited telomerase activity with high potency, which was not observed with Scramble or Mismatch oligonucleotides. DTPA-conjugation and 111In-labeling did not change telomerase inhibition. In telomerase-positive cancer cells, unlabeled Match oligonucleotides had no effect on survival, however, 111In-labeled Match oligonucleotides significantly reduced clonogenic survival and upregulated the DNA damage marker γH2AX. Minimal radiotoxicity and DNA damage was observed in telomerase-negative cells exposed to 111In-Match oligonucleotides. Match oligonucleotides localized in close proximity to nuclear Cajal bodies in telomerase-positive cells. In comparison with Match oligonucleotides, 111In-Scramble or 111In-Mismatch oligonucleotides demonstrated reduced retention and negligible impact on cell survival. This study indicates the therapeutic activity of radiolabeled oligonucleotides that specifically target hTR through potent telomerase inhibition and DNA damage induction in telomerase-expressing cancer cells and paves the way for the development of novel oligonucleotide radiotherapeutics targeting telomerase-positive cancers.

Significance:
These findings present a novel radiolabeled oligonucleotide for targeting telomerase-positive cancer cells that exhibits dual activity by simultaneously inhibiting telomerase and promoting radiation-induced genomic DNA damage.
HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer
Authors: Fukumoto Takeshi , Fatkhutdinov Nail , Zundell Joseph A. , Tcyganov Evgenii N. , Nacarelli Timothy , Karakashev Sergey , Wu Shuai , Liu Qin , Gabrilovich Dmitry I. , Zhang Rugang 
Published: July 2019

Abstract

ARID1A, encoding a subunit of the SWI/SNF complex, is the most frequently mutated epigenetic regulator in human cancers and is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), a disease that currently has no effective therapy. Inhibition of histone deacetylase 6 (HDAC6) suppresses the growth of ARID1A-mutated tumors and modulates tumor immune microenvironment. Here, we show that inhibition of HDAC6 synergizes with anti-PD-L1 immune checkpoint blockade in ARID1A-inactivated ovarian cancer. ARID1A directly repressed transcription of CD274, the gene encoding PD-L1. Reduced tumor burden and improved survival were observed in ARID1Aflox/flox/PIK3CAH1047R OCCC mice treated with the HDAC6 inhibitor ACY1215 and anti-PD-L1 immune checkpoint blockade as a result of activation and increased presence of IFNγ-positive CD8 T cells. We confirmed that the combined treatment limited tumor progression in a cytotoxic T-cell–dependent manner, as depletion of CD8+ T cells abrogated these antitumor effects. Together, these findings indicate that combined HDAC6 inhibition and immune checkpoint blockade represents a potential treatment strategy for ARID1A-mutated cancers.

Significance:
These findings offer a mechanistic rationale for combining epigenetic modulators and existing immunotherapeutic interventions against a disease that has been so far resistant to checkpoint blockade as a monotherapy.
See related commentary by Prokunina-Olsson, p. 5476
Deciphering the Role of Protein Kinase D1 (PKD1) in Cellular Proliferation
Authors: Youssef Ilige , Ricort Jean-Marc 
Published: July 2019

AbstractProtein kinase D1 (PKD1) is a serine/threonine kinase that belongs to the calcium/calmodulin-dependent kinase family, and is involved in multiple mechanisms implicated in tumor progression such as cell motility, invasion, proliferation, protein transport, and apoptosis. While it is expressed in most tissues in the normal state, PKD1 expression may increase or decrease during tumorigenesis, and its role in proliferation is context-dependent and poorly understood. In this review, we present and discuss the current landscape of studies investigating the role of PKD1 in the proliferation of both cancerous and normal cells. Indeed, as a potential therapeutic target, deciphering whether PKD1 exerts a pro- or antiproliferative effect, and under what conditions, is of paramount importance.
Physiological Biomimetic Culture System for Pig and Human Heart Slices
Authors: Ou Qinghui , Jacobson Zoë , Abouleisa Riham R.E. , Tang Xian-Liang , Hindi Sajedah M. , Kumar Ashok , Ivey Kathryn N. , Giridharan Guruprasad , El-Baz Ayman , Brittian Kenneth , Rood Benjamin , Lin Ying-Hsi , Watson Samuel A. , Perbellini Filippo , McKinsey Timothy A. , Hill Bradford G. , Jones Steven P. , Terracciano Cesare M. , Bolli Roberto , Mohamed Tamer M.A. 
Published: July 2019

Rationale:
Preclinical testing of cardiotoxicity and efficacy of novel heart failure therapies faces a major limitation: the lack of an in situ culture system that emulates the complexity of human heart tissue and maintains viability and functionality for a prolonged time.

Objective:
To develop a reliable, easily reproducible, medium-throughput method to culture pig and human heart slices under physiological conditions for a prolonged period of time.

Methods and Results:
Here, we describe a novel, medium-throughput biomimetic culture system that maintains viability and functionality of human and pig heart slices (300 µm thickness) for 6 days in culture. We optimized the medium and culture conditions with continuous electrical stimulation at 1.2 Hz and oxygenation of the medium. Functional viability of these slices over 6 days was confirmed by assessing their calcium homeostasis, twitch force generation, and response to β-adrenergic stimulation. Temporal transcriptome analysis using RNAseq at day 2, 6, and 10 in culture confirmed overall maintenance of normal gene expression for up to 6 days, while over 500 transcripts were differentially regulated after 10 days. Electron microscopy demonstrated intact mitochondria and Z-disc ultra-structures after 6 days in culture under our optimized conditions. This biomimetic culture system was successful in keeping human heart slices completely viable and functionally and structurally intact for 6 days in culture. We also used this system to demonstrate the effects of a novel gene therapy approach in human heart slices. Furthermore, this culture system enabled the assessment of contraction and relaxation kinetics on isolated single myofibrils from heart slices after culture.

Conclusions:
We have developed and optimized a reliable medium-throughput culture system for pig and human heart slices as a platform for testing the efficacy of novel heart failure therapeutics and reliable testing of cardiotoxicity in a 3-dimensional heart model.
Effect of Intensive and Standard Clinic‐Based Hypertension Management on the Concordance Between Clinic and Ambulatory Blood Pressure and Blood Pressure Variability in SPRINT
Authors: Ghazi Lama , Pajewski Nicholas M. , Rifkin Dena E. , Bates Jeffrey T. , Chang Tara I. , Cushman William C. , Glasser Stephen P. , Haley William E. , Johnson Karen C. , Kostis William J. , Papademetriou Vasilios , Rahman Mahboob , Simmons Debra L. , Taylor Addison , Whelton Paul K. , Wright Jackson T. , Bhatt Udayan Y. , Drawz Paul E. 
Published: July 2019

Background

Blood pressure (
BP
) varies over time within individual patients and across different
BP
measurement techniques. The effect of different
BP
targets on concordance between
BP
measurements is unknown. The goals of this analysis are to evaluate concordance between (1) clinic and ambulatory
BP
, (2) clinic visit‐to‐visit variability and ambulatory
BP
variability, and (3) first and second ambulatory
BP
and to evaluate whether different clinic targets affect these relationships.

Methods and Results

The SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory
BP
monitoring ancillary study obtained ambulatory
BP
readings in 897 participants at the 27‐month follow‐up visit and obtained a second reading in 203 participants 293±84 days afterward. There was considerable lack of agreement between clinic and daytime ambulatory systolic
BP
with wide limits of agreement in Bland‐Altman plots of −21 to 34 mm Hg in the intensive‐treatment group and −26 to 32 mm Hg in the standard‐treatment group. Overall, there was poor agreement between clinic visit‐to‐visit variability and ambulatory
BP
variability with correlation coefficients for systolic and diastolic
BP
all <0.16. We observed a high correlation between first and second ambulatory
BP
; however, the limits of agreement were wide in both the intensive group (−27 to 21 mm Hg) and the standard group (−23 to 20 mm Hg).

Conclusions

We found low concordance in
BP
and
BP
variability between clinic and ambulatory
BP
and second ambulatory
BP
. Results did not differ by treatment arm. These results reinforce the need for multiple
BP
measurements before clinical decision making.
Anglican Indigenization and Contextualization in Colonial Hong Kong: Comparative Case Studies of St. John’s Cathedral and St. Mary’s Church
Authors: Ellis James 
Published: July 2019

Abstract
The British Empire expanded into East Asia during the early years of the Protestant Mission Movement in China, one of history’s greatest cross-cultural encounters. Anglicans, however, did not accommodate local Chinese culture when they built St. John’s Cathedral in the British Crown Colony of Hong Kong. St. John’s had a prototypical English style and was a gathering place for the colony’s political and social elites, strengthening the new social order. The Cathedral spoke a Western architectural language that local residents could not understand and many saw Christianity as a strange, imposing, foreign religion. As indigenous Chinese Christians assumed leadership of Hong Kong’s Anglican Church, ecclesial architecture took on more Chinese elements, a transition epitomized by St. Mary’s Church, a Chinese Renaissance masterpiece featuring symbols from Taoism, Buddhism, and Chinese folk religions. This essay analyzes the contextualization of Hong Kong’s Anglican architecture, which made Christian concepts more relevant to the indigenous community.
The Stroke Stigma Scale: a reliable and valid stigma measure in patients with stroke
Authors: Zhu Minfang , Zhou Hongzhen , Zhang Weibin , Deng Yingying , Wang Xiaoyan , Bai Xuejie , Li Muling , Hu Ruidan , Hou Jiakun , Liu Yangyang 
Published: July 2019

Objective: The objective of the study is to analyse the psychometric properties of the Stroke Stigma Scale, a novel scale to assess perceived stigma of patients with stroke. Design: This is a psychometric study. Setting: Neurology or rehabilitation units in three hospitals in China. Subjects: A total of 288 patients with stroke. Interventions: None. Measures: The content validity of the Stroke Stigma Scale was assessed through expert consultation. Criterion validity was evaluated based on the scale’s relationships with the Stigma Scale for Chronic Illness and the Self-rating Depression Scale. Construct validity was assessed using exploratory factor analysis, and internal consistency was tested with Cronbach’s α. Results: The final version Stroke Stigma Scale consists of 16 items. It showed strong positive correlations with both the Stigma Scale for Chronic Illness ( ρ = 0.89, P < 0.001) and the Self-rating Depression Scale ( ρ = 0.82, P < 0.001). The exploratory factor analysis revealed four components of the Stroke Stigma Scale: internalized stigma, physical impairment, discrimination experience, and social isolation, which were strongly associated with our perceived stroke stigma model. Cronbach’s α for the total scale was 0.92, and that of each subscale was 0.77–0.86. The test–retest reliability with intra-class correlation coefficients of the total scale was 0.92 ( P < 0.001), and intra-class correlation coefficients of each subscale were 0.74–0.89 ( P < 0.001). Conclusions: The Stroke Stigma Scale is a reliable and valid measure of perceived stigma in patients with stroke, which may be useful in stigma prevention and stroke rehabilitation.
Importance of stabilization of the neonatal transport network in critically ill neonates
Authors: Xu Xiao-Jing , Li Li-Na , Wu Wen-Yan 
Published: July 2019

Objective This study aimed to investigate how to stabilize the condition of critically ill neonates within the neonatal transport network. Methods A total of 243 critically ill newborns in four hospitals involved in the transport network were enrolled. The newborns were divided into the research and control groups. In the research group, medical staff underwent theoretical training, and neonatal intensive care unit (NICU) professionals participated and provided on-site guidance on delivery of high-risk infants. Delivery of high-risk neonates in the control group was conventionally managed in local hospitals, and neonates were transferred after a phone call to the NICU. Results Gestational age and body weight were lower, and dexamethasone use was higher in the research group than in the control group. The proportions of neonates who underwent mask pressure, endotracheal intubation, pulmonary surfactant application, and chest compressions were higher, and those with dyspnea and nervous system abnormalities were lower in the research group than in the control group. Blood gas and sugar levels were better in the research group than in the control group. Conclusion Strengthening professional training and participation of professional NICU staff in childbirth can improve the conditions of high-risk neonates and increase safety of their transportation.
Practice analysis: Critical reflexivity on discourses constraining socially transformative occupational therapy practices
Authors: Farias Lisette , Rudman Debbie Laliberte 
Published: July 2019

Statement of context: Despite recognition of the potential of occupation for enacting social transformation, occupational therapy continues to struggle in developing and enacting practice approaches that address sociopolitical barriers to people’s right to engage in occupations. Critical reflection on practice: Ways of thinking and writing about problems and solutions, that is discourses, shape occupational therapy practices. This article draws attention to three dominant discourses that constrain the development of occupational therapy practices aimed at social transformation, specifically, individualism, healthism and managerialism. Implications for practice: Examining discourses that bound occupational therapy practice can open spaces for alternative ways of thinking and more socially responsive practices addressing sociopolitical barriers to occupation.
Minimum 5-Year Outcomes of Arthroscopic Hip Labral Reconstruction With Nested Matched-Pair Benchmarking Against a Labral Repair Control Group
Authors: Domb Benjamin G. , Battaglia Muriel R. , Perets Itay , Lall Ajay C. , Chen Austin W. , Ortiz-Declet Victor , Maldonado David R. 
Published: July 2019

Background: Labral reconstruction has demonstrated short-term benefit for the treatment of irreparable labral tears. Nonetheless, there is a scarcity of evidence for midterm outcomes of this treatment. Hypotheses: Arthroscopic segmental reconstruction in the setting of irreparable labral tears would show improvement in patient-reported outcomes (PROs) and high patient satisfaction at minimum 5-year follow-up. Second, primary labral reconstruction (PLRECON) would result in similar improvement in PROs at minimum 5-year follow-up when compared with a matched-pair primary labral repair (PLREPAIR) control group. Study Design: Cohort study; Level of evidence, 3. Methods: Data from February 2008 to April 2013 were retrospectively reviewed. Patients were included if they underwent hip arthroscopy for segmental labral reconstruction in the setting of irreparable labral tear and femoroacetabular impingement, with minimum 5-year follow-up for modified Harris Hip Score, Nonarthritic Hip Score, Hip Outcome Score–Sports Specific Subscale, patient satisfaction, and visual analog scale for pain. Exclusion criteria were Tönnis osteoarthritis grade >1, prior hip conditions, or workers’ compensation claims. PLRECON cases were matched in a 1:3 ratio to a PLREPAIR control group based on age ±5 years, sex, and body mass index ±5 kg/m2. Results: Twenty-eight patients were eligible for the study, of which 23 (82.14%) had minimum 5-year follow-up. The authors found significant improvement from preoperative to latest follow-up in all outcome measures recorded: 17.8-point increase in modified Harris Hip Score ( P = .002), 22-point increase in Nonarthritic Hip Score ( P < .001), 25.4-point increase in Hip Outcome Score–Sports Specific Subscale ( P = .003), and a 2.9-point decrease in visual analog scale pain ratings ( P < .001). Mean patient satisfaction was 7.1 out of 10. In the nested matched-pair analysis, 17 patients who underwent PLRECON were matched to a control group of 51 patients who underwent PLREPAIR. PLRECON demonstrated comparable survivorship and comparable improvements in all PROs with the exception of patient satisfaction (6.7 vs 8.5, P = .04). Conclusion: Hip arthroscopy with segmental labral reconstruction resulted in significant improvement in PROs at minimum 5-year follow-up. PLRECON reached comparable functional outcomes when compared with a benchmark PLREPAIR control group but demonstrated lower patient satisfaction at latest follow-up.
Anterior and Rotational Knee Laxity Does Not Affect Patient-Reported Knee Function 2 Years After Anterior Cruciate Ligament Reconstruction
Authors: Magnussen Robert , Reinke Emily K. , Huston Laura J. ,   MOON Knee Group, Andrish Jack T. , Cox Charles L. , Dunn Warren R. , Flanigan David C. , Hewett Timothy , Jones Morgan H. , Kaeding Christopher C. , Lorring Dawn , Matava Matthew J. , Parker Richard D. , Pedroza Angela , Preston Emily , Richardson Brian , Schroeder Bettina , Smith Matthew V. , Wright Rick W. , Spindler Kurt P. 
Published: July 2019

Background:While a primary goal of anterior cruciate ligament (ACL) reconstruction is to reduce pathologically increased anterior and rotational knee laxity, the relationship between knee laxity after ACL reconstruction and patient-reported knee function remains unclear.Hypothesis:There would be no significant correlation between the degree of residual anterior and rotational knee laxity and patient-reported outcomes (PROs) 2 years after primary ACL reconstruction.Study Design:Cross-sectional study; Level of evidence, 3.Methods:From a prospective multicenter nested cohort of patients, 433 patients younger than 36 years of age injured in sports with no history of concomitant ligament surgery, revision ACL surgery, or surgery of the contralateral knee were identified and evaluated at a minimum 2 years after primary ACL reconstruction. Each patient underwent Lachman and pivot-shift evaluation as well as a KT-1000 arthrometer assessment along with Knee injury and Osteoarthritis Outcome Score and subjective International Knee Documentation Committee (IKDC) scores. A proportional odds logistic regression model was used to predict each 2-year PRO score, controlling for preoperative score, age, sex, body mass index, smoking, Marx activity score, education, subsequent surgery, meniscal and cartilage status, graft type, and range of motion asymmetry. Measures of knee laxity were independently added to each model to determine correlation with PROs.Results:Side-to-side manual Lachman differences were IKDC A in 246 (57%) patients, IKDC B in 183 (42%) patients, and IKDC C in 4 (<1%) patients. Pivot-shift was classified as IKDC A in 209 (48%) patients, IKDC B in 183 (42%) patients, and IKDC C in 11 (2.5%) patients. The mean side-to-side KT-1000 difference was 2.0 ± 2.6 mm. No significant correlations were noted between pivot-shift or anterior tibial translation as assessed by Lachman or KT-1000 and any PRO. All predicted differences in PROs based on IKDC A versus B pivot-shift and anterior tibial translation were less than 4 points.Conclusion:Neither the presence of IKDC A versus B pivot-shift nor increased anterior tibial translation of up to 6 mm is associated with clinically relevant decreases in PROs 2 years after ACL reconstruction.
Scapular Spine Dimensions and Suitability as a Glenoid Bone Graft Donor Site
Authors: Rohman Eric , Gronbeck Kyle , Tompkins Marc , Mittelsteadt Marcus , Kirkham James A. , Arciero Robert A. 
Published: July 2019

Background: Current structural bone graft options used for glenoid augmentation in glenohumeral instability have known drawbacks. The scapular spine may be a possible alternative graft choice, but its dimensions and anatomy are not fully reported. Hypothesis: The scapular spine’s harvestable graft dimensions will be similar to harvestable dimensions of the coracoid and iliac crest. Study Design: Descriptive laboratory study. Methods: The scapular spine, coracoid, and iliac crest dimensions were recorded and compared bilaterally in 50 patients with 3-dimensional computed tomography imaging. The portion of the scapular spine with the largest harvestable dimensions was quantified and its location defined. Measurements were independently taken by 2 investigators and averaged for the final result. Results: The scapular spine has 81.5 mm of harvestable length and a “flare” located approximately 49.6 mm lateral to the medial scapular border, where the widest harvestable cross section is located (mean harvestable dimensions: 10.9-mm height, 11.5-mm width). Mean coracoid dimensions were 24-mm length, 14.2-mm height, and 10.6-mm width. Mean iliac crest width was 14.7 mm. In sum, 96% of scapular spines, 85% of coracoids, and 100% of iliac crests exceeded minimum dimensions of 8 mm × 8 mm × 20 mm. The coronal radius of curvature of the glenoid was significantly different from the corresponding plane of all measured structures. Conclusion/Clinical Relevance: The scapular spine has dimensions similar to the coracoid and iliac crest in the majority of patients and is therefore appropriate for further investigation as a potential graft choice in glenohumeral instability. A harvest location 49.6 mm lateral to the medial scapular border will provide the largest cross-sectional graft while avoiding the acromial base.