bluuebunny/crossref_metadata_2025_split huggingface dataset:
Will an innovative connected AideSmart! app-based multiplex, point-of-care screening strategy for HIV and related coinfections affect timely quality antenatal screening of rural Indian women? Results from a cross-sectional study in India
Authors: Pant Pai Nitika , Daher Jana , Prashanth HR , Shetty Achal , Sahni Rani Diana , Kannangai Rajesh , Abraham Priya , Isaac Rita 
Published: October 2018

ObjectivesIn rural pregnant Indian women, multiple missed antenatal screening opportunities due to inadequate public health facility-based screening result in undiagnosed HIV and sexually transmitted bloodborne infections (STBBIs) and conditions (anaemia). Untreated infections complicate pregnancy management, precipitate adverse outcomes and risk mother-to-child transmission. Additionally, a shortage of trained doctors, rural women’s preference for home delivery and health illiteracy affect health service delivery. To address these issues, we developed AideSmart!, an innovative, app-based, cloud-connected, rapid screening strategy that offers multiplex screening for STBBIs and anaemia at the point of care. It offers connectivity, integration, expedited communications and linkages to clinical care throughout pregnancy.MethodsIn a cross-sectional study, we evaluated the AideSmart! strategy for feasibility, acceptability, preference and impact. We trained 15 healthcare professionals (HCPs) to offer the AideSmart! strategy to 510 pregnant women presenting for care to outreach rural service units of Christian Medical College, Vellore, India.ResultsWith the AideSmart! screening strategy, we recorded an acceptability of 100% (510/510), feasibility (completion rate) of 91.6% (466/510) and preference of 73%. We detected 239 infections/conditions (239/510, 46.8%) at the point-of-care, of which 168 (168/239; 70%) were lab confirmed, staged and treated rapidly. Of the 168 confirmed infections/conditions, 127 were anaemia, 11 Trichomonas and 30 hepatitis B virus (HBV) (25 resolved naturally, 5 active infections). Four infants (4/5; 80%) were prophylaxed for HBV and were declared disease-free at 9 months. Recruited participants were young; mean age was 24 years (range: 17–40) and 74% (376/510) were in their second trimester. Furthermore, 95% of the participants were retained throughout their pregnancy.ConclusionThe AideSmart! strategy was deemed feasible to operationalise by HCPs. It was accepted and preferred by participants, resulting in timely screening and treatment of HIV/STIs and anaemia, preventing mother-to-child transmission. The strategy could be reverse-innovated to any context to maximise its health impact.
Low‐dose intravenous lipid emulsion as a safe treatment for lipophilic intoxications in five cats
Authors: Pelizzola Marco , Mattavelli Clara , Troìa Roberta , Murgia Elsa , Giunti Massimo 
Published: October 2018

The use of a low‐dose infusion of intravenous lipid emulsion (ILE) in five young cats presented with acute neurotoxicity is reported. Suspected toxic compounds were permethrin (three, dermal), fipronil/eprinomectin/praziquantel (one, oral) and milbemycin (one, oral). Cats presented with acute onset of generalised tremors of variable severity. Initial treatment included toxin decontamination whenever possible, and control of neurological signs by administration of benzodiazepine and eventually a continuous rate infusion of propofol. Due to persisting clinical signs, a low‐dose ILE therapy was additionally given. Discontinuation of treatment, once a resolution of neurological signs was achieved, ranged between two and nine hours from hospital admission. All the cats fully recovered and were discharged within 18–92 hours. No side effects were noticed and follow‐up was normal. The authors report the use of a low‐dose infusion of ILE as an adjunctive and safe treatment for the management of lipophilic intoxications in cats.
Solitary spinal nephroblastoma progressing to multifocal disease in a dog
Authors: Yu Sonya , Hoffmann Karon , Taylor David , Lurie David 
Published: October 2018

A two‐ year‐old neutered Labrador dog was evaluated for acute onset hindlimb paresis and proprioceptive deficits. Spinal MRI revealed a lesion at the level of T9–T10, from which a presumptive diagnosis of spinal nephroblastoma was made. The dog showed clinical improvement after receiving neoadjuvant stereotactic radiotherapy but re‐presented six weeks later with neurological deterioration. In addition to the primary lesion, a repeat MRI study revealed lesions at T6–T7 and T12. The dog was euthanased and multiple intradural, extramedullary spinal cord lesions were found at postmortem examination. Histopathological analysis of the lesions confirmed spinal nephroblastoma. This report substantiates the likelihood of intraspinal metastases of nephroblastoma occurring in the dog.
Serum- and Glucocorticoid-induced Kinase Sgk1 Directly Promotes the Differentiation of Colorectal Cancer Cells and Restrains Metastasis
Authors: Lee Lennard Y.W. , Woolley Connor , Starkey Thomas , Biswas Sujata , Mirshahi Tia , Bardella Chiara , Segditsas Stefania , Irshad Shazia , Tomlinson Ian 
Published: October 2018

Abstract

Purpose:
The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, because in colorectal cancer, the degree of differentiation of a tumor is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer, there is marked downregulation of SGK1 compared with normal tissue.
Experimental Design: An inducible SGK1 viral overexpression system was utilized to induce reexpression of SGK1 in colorectal cancer cell lines. Transcriptomic and phenotypic analyses of these colorectal cancer lines was performed and validation in mouse and human cohorts was performed.

Results:
We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Reexpression of SGK1 in colorectal cancer cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated, in part, by SGK1-induced PKP3 expression and increased degradation of MYC.

Conclusions:
Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit colorectal cancer metastasis.
The Number of Screening Cycles Needed to Reduce Prostate Cancer Mortality in the Finnish Section of the European Randomized Study of Prostate Cancer (ERSPC)
Authors: Pakarainen Tomi , Nevalainen Jaakko , Talala Kirsi , Taari Kimmo , Raitanen Jani , Kujala Paula , Stenman Ulf-Håkan , Tammela Teuvo L.J. , Auvinen Anssi 
Published: October 2018

Abstract

Purpose:
The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer mortality by PSA-based screening. The aim of the study is to evaluate screening effect on prostate cancer incidence and mortality in relation to number of screening rounds attended.
Experimental Design: The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance, then remained among the once-screened until the second screen and similarly for the possible third round. The control arm was the reference. Follow-up started at randomization and ended at death, emigration, or end of 2013. Prostate cancer incidence and mortality, as well lung cancer and overall mortality were evaluated.

Results:
Prostate cancer incidence was increased among screened men, but was not directly related to the number of screening rounds. Prostate cancer mortality was decreased in men screened twice or three times, but did not materially differ in those who did not attend the screening, and in men screened once compared with the control arm. The largest mortality reduction was in men screened three times [HR 0.17; 95% confidence interval (CI), 0.09–0.33]. However, a reduction was also seen in lung cancer (HR 0.59; 95% CI, 0.47–0.73) and overall mortality (HR 0.56; 95% CI, 0.52–0.60).

Conclusions:
Assuming a similar relative reduction being due to selection bias and screening in prostate cancer as other causes of death (40% reduction), approximately half of the observed prostate cancer mortality reduction by repeated screening is likely to be noncausal and a real screening effect may account for up to 40% reduction in men screened three times. Prostate cancer mortality reduction can only be achieved by repeated screening cycles.
Enhanced Antitumor Efficacy of Oncolytic Adenovirus–loaded Menstrual Blood–derived Mesenchymal Stem Cells in Combination with Peripheral Blood Mononuclear Cells
Authors: Moreno Rafael , Fajardo Carlos Alberto , Farrera-Sal Marti , Perisé-Barrios Ana Judith , Morales-Molina Alvaro , Al-Zaher Ahmed Abdullah , García-Castro Javier , Alemany Ramon 
Published: October 2018

Abstract
Several studies have evaluated the efficacy of using human oncolytic adenovirus (OAdv)–loaded mesenchymal stem cells (MSC) for cancer treatment. For example, we have described the antitumor efficacy of CELYVIR, autologous bone marrow–mesenchymal stem cells infected with the OAdv ICOVIR-5, for treatment of patients with neuroblastoma. Results from this clinical trial point out the role of the immune system in the clinical outcome. In this context, a better understanding of the immunophenotypic changes of human MSCs upon adenoviral infection and how these changes affect human autologous or allogeneic peripheral blood mononuclear cells (PBMC) could guide strategies to improve the antitumor efficacy of infected MSCs. In this work, we show how infection by an OAdv induces toll-like receptor 9 overexpression and activation of the NFĸB pathway in menstrual blood–derived MSCs, leading to a specific cytokine secretion profile. Moreover, a proinflammatory environment, mainly mediated by monocyte activation that leads to the activation of both T cells and natural killer cells (NK cell), is generated when OAdv-loaded MSCs are cocultured with allogeneic PBMCs. This combination of allogeneic PBMCs and OAdv-loaded MSCs enhances antitumor efficacy both in vitro and in vivo, an effect partially mediated by monocytes and NK cells. Altogether our results demonstrate not only the importance of the immune system for the OAdv-loaded MSCs antitumor efficacy, but in particular the benefits of using allogeneic MSCs for this therapy.
Multiplex Three-Dimensional Mapping of Macromolecular Drug Distribution in the Tumor Microenvironment
Authors: Lee Steve Seung-Young , Bindokas Vytautas P. , Kron Stephen J. 
Published: October 2018

Abstract
Macromolecular cancer drugs such as therapeutic antibodies and nanoparticles are well known to display slow extravasation and incomplete penetration into tumors, potentially protecting cancer cells from therapeutic effects. Conventional assays to track macromolecular drug delivery are poorly matched to the heterogeneous tumor microenvironment, but recent progress on optical tissue clearing and three-dimensional (3D) tumor imaging offers a path to quantitative assays with cellular resolution. Here, we apply transparent tissue tomography (T3) as a tool to track perfusion and delivery in the tumor and to evaluate target binding and vascular permeability. Using T3, we mapped anti–programmed cell death protein-ligand 1 (PD-L1) antibody distribution in whole mouse tumors. By measuring 3D penetration distances of the antibody drug out from the blood vessel boundaries into the tumor parenchyma, we determined spatial pharmacokinetics of anti–PD-L1 antibody drugs in mouse tumors. With multiplex imaging of tumor components, we determined the distinct distribution of anti–PD-L1 antibody drug in the tumor microenvironment with different PD-L1 expression patterns. T3 imaging revealed CD31+ capillaries are more permeable to anti–PD-L1 antibody transport compared with the blood vessels composed of endothelium supported by vascular fibroblasts and smooth muscle cells. T3 analysis also confirmed that isotype IgG antibody penetrates more deeply into tumor parenchyma than anti-Her2 or anti-EGFR antibody, which were restrained by binding to their respective antigens on tumor cells. Thus, T3 offers simple and rapid access to 3D, quantitative maps of macromolecular drug distribution in the tumor microenvironment, offering a new tool for development of macromolecular cancer therapeutics.
UNC-45A Is a Novel Microtubule-Associated Protein and Regulator of Paclitaxel Sensitivity in Ovarian Cancer Cells
Authors: Mooneyham Ashley , Iizuka Yoshie , Yang Qing , Coombes Courtney , McClellan Mark , Shridhar Vijayalakshmi , Emmings Edith , Shetty Mihir , Chen Liqiang , Ai Teng , Meints Joyce , Lee Michael K. , Gardner Melissa , Bazzaro Martina 
Published: October 2018

AbstractUNC-45A, a highly conserved member of the UCS (UNC45A/CRO1/SHE4P) protein family of cochaperones, plays an important role in regulating cytoskeletal-associated functions in invertebrates and mammalian cells, including cytokinesis, exocytosis, cell motility, and neuronal development. Here, for the first time, UNC-45A is demonstrated to function as a mitotic spindle-associated protein that destabilizes microtubules (MT) activity. Using in vitro biophysical reconstitution and total internal reflection fluorescence microscopy analysis, we reveal that UNC-45A directly binds to taxol-stabilized MTs in the absence of any additional cellular cofactors or other MT-associated proteins and acts as an ATP-independent MT destabilizer. In cells, UNC-45A binds to and destabilizes mitotic spindles, and its depletion causes severe defects in chromosome congression and segregation. UNC-45A is overexpressed in human clinical specimens from chemoresistant ovarian cancer and that UNC-45A–overexpressing cells resist chromosome missegregation and aneuploidy when treated with clinically relevant concentrations of paclitaxel. Lastly, UNC-45A depletion exacerbates paclitaxel-mediated stabilizing effects on mitotic spindles and restores sensitivity to paclitaxel.Implications:These findings reveal novel and significant roles for UNC-45A in regulation of cytoskeletal dynamics, broadening our understanding of the basic mechanisms regulating MT stability and human cancer susceptibility to paclitaxel, one of the most widely used chemotherapy agents for the treatment of human cancers.
Single-Nucleotide Polymorphism of the
MLX
Gene Is Associated With Takayasu Arteritis
Authors: Tamura Natsuko , Maejima Yasuhiro , Matsumura Takayoshi , Vega Rick B. , Amiya Eisuke , Ito Yusuke , Shiheido-Watanabe Yuka , Ashikaga Takashi , Komuro Issei , Kelly Daniel P. , Hirao Kenzo , Isobe Mitsuaki 
Published: October 2018

Background:

Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown pathogenesis. Genome-wide association studies revealed that single-nucleotide polymorphisms in the
MLX
gene encoding the MLX (Max-like protein X) transcription factor are significantly associated with TAK in Japanese patients.
MLX
single-nucleotide polymorphism rs665268 is a missense mutation causing the Q139R substitution in the DNA-binding site of MLX.

Methods:

To elucidate the hypothesis that the single-nucleotide polymorphism of the
MLX
gene plays a critical role in the development of TAK, we conducted clinical and laboratory analyses.

Results:

We show that rs665268 significantly correlated with the severity of TAK, including the number of arterial lesions and morbidity of aortic regurgitation; the latter may be attributed to the fact that
MLX
mRNA expression was mostly detected in the aortic valve. Furthermore, the Q139R mutation caused structural changes in MLX, which resulted in enhanced formation of a heterodimer with MondoA, upregulation of TXNIP (thioredoxin-interacting protein) expression, and increase in the activity of the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome and cellular oxidative stress. Furthermore, autophagy, which negatively regulates inflammasome activation, was suppressed by the Q139R mutation in MLX. The MLX-Q139R mutant significantly induced macrophage proliferation and macrophage–endothelium interaction, which was abolished by the treatment with SBI-477, an inhibitor of MondoA nuclear translocation. Our findings suggest that the Q139R substitution in MLX plays a crucial role in the pathogenesis of TAK.

Conclusions:
MLX-Q139R mutation plays a crucial role in the pathogenesis of TAK through promoting inflammasome formation.
Clinical Outcome of Patients With Inducible Capillary Blood Flow Abnormalities During Demand Stress in the Presence or Absence of Angiographic Coronary Disease
Authors: Kutty Shelby , Bisselou Moukagna Karl Stessy , Craft Mary , Shostrom Valerie , Xie Feng , Porter Thomas R. 
Published: October 2018

Background:
Our aim was to determine the cardiovascular outcome of patients with capillary blood flow (CBF) abnormalities detected during demand stress in the absence of obstructive coronary artery disease.

Methods and Results:

We identified 380 consecutive patients referred for coronary angiography (CA) after dobutamine or exercise stress echocardiography (SE) between 2008 and 2013 performed with real-time perfusion imaging to examine myocardial CBF with a continuous ultrasound contrast infusion. Patients with left ventricular ejection fraction <40% were excluded. There were 3 groups based on results: positive SE/negative CA, patients who had abnormal regional CBF but no significant angiographic disease; positive SE/positive CA, those with abnormal CBF and significant disease on subsequent CA; and negative SE/negative CA, patients with normal CBF and negative CA. Event-free survival examining death and nonfatal myocardial infarction was compared. Median follow-up was 4 years. There were 91 positive SE/negative CA, 189 positive SE/positive CA, and 100 negative SE/negative CA patients over the study period. The positive SE/negative CA patients were more frequently women and had a lower prevalence of hypertension and hyperlipidemia (all
P
<0.001). Analysis of event-free survival with Cox regression demonstrated that death/nonfatal myocardial infarction rates were higher in the positive SE/positive CA (hazard ratio, 2.10; CI, 1.02–4.29) and positive SE/negative CA (hazard ratio, 2.02; CI, 0.99–4.31) groups when compared with negative SE/negative CA groups.

Conclusions:
Patients with inducible CBF abnormalities in the absence of significant obstructive disease at CA still have similar death/nonfatal myocardial infarction rates as those with significant disease at CA.
Prognostic Importance of Left Ventricular Mechanical Dyssynchrony in Predicting Cardiovascular Death in the General Population
Authors: Modin Daniel , Biering-Sørensen Sofie Reumert , Møgelvang Rasmus , Jensen Jan Skov , Biering-Sørensen Tor 
Published: October 2018

Background:
Cardiovascular death (CVD) is a leading cause of death and constitutes a major burden on society. Left ventricular mechanical dyssynchrony (LVMD), evaluated as SD of time to peak regional longitudinal strain, is a capable predictor of many cardiovascular outcomes related to CVD, including ventricular arrhythmias, but the prognostic utility of LVMD in the general population is unknown. Hence, this study sought to determine the prognostic value of LVMD in the general population in predicting CVD.

Methods and Results:

A total of 1138 participants underwent a general health examination and an echocardiographic examination including speckle tracking analysis with subsequent calculation of LVMD from time-to-peak regional strain. Primary end point was CVD, and secondary end point was noncardiovascular death. Follow-up was 100%. During a median follow-up of 11.1 years (interquartile range: 10.2–11.3 years), 62 participants suffered CVD (5.5%) while 131 participants experienced noncardiovascular death (11.5%). LVMD was an independent predictor of CVD (subdistribution hazard ratio, 1.04; 95% CI, 1.01–1.06;
P
=0.004, per 10-ms increase) in competing risk regression treating noncardiovascular death as a competing risk and retained prognostic capability after extensive multivariable adjustment. LVMD was not a significant predictor of noncardiovascular death. LVMD added incremental prognostic information in predicting CVD beyond the Systematic Coronary Risk Evaluation risk chart and a modified version of the American College of Cardiology/American Heart Association Pooled Cohort Equation.

Conclusions:
Left ventricular mechanical dyssynchrony adds incremental prognostic information in addition to established risk factors in prediction of CVD in individuals from the general population without atrial fibrillation and significant valvular disease.
Predictors of Unexpected Early Reocclusion After Successful Mechanical Thrombectomy in Acute Ischemic Stroke Patients
Authors: Mosimann Pascal J. , Kaesmacher Johannes , Gautschi Dominic , Bellwald Sebastian , Panos Leonidas , Piechowiak Eike , Dobrocky Tomas , Zibold Felix , Mordasini Pasquale , El-Koussy Marwan , Wiest Roland , Bervini David , Wagner Franca , Arnold Marcel , Jung Simon , Galimanis Aikaterini , Gralla Jan , Fischer Urs 
Published: October 2018

Background and Purpose—
Sustained successful reperfusion is an important prognostic factor for good clinical outcome in acute ischemic stroke. We aimed to identify the prevalence, clinical impact, and predictors of early reocclusion after initially successful thrombectomies within a prospective cohort.

Methods—
A total of 711 stroke patients with successful reperfusion (modified Thrombolysis in Cerebral Infarction, 2b/3) followed with magnetic resonance or computed tomographic angiography at 24 to 48 hours were included. Multivariable logistic regression analysis was used to evaluate associated factors and clinical impact. Results are displayed as adjusted odds ratio (aOR) and 95% CI. Improvement in accuracy of additional imaging findings on angiography control runs after the intervention was evaluated by area under the curve.

Results—

Early reocclusion was observed in 16 of 711 successfully reperfused patients (2.3%; 95% CI, 1.1–3.3; median delay: 20 hours). Suggestive predictors were higher platelets on admission (aOR, 1.01; 95% CI, 1.01–1.02), prestroke functional dependence (aOR, 7.12; 95% CI, 1.49–34.03), and stroke of undetermined or other specified pathogenesis in the TOAST classification (aOR, 7.19; 95% CI, 1.10–47.05 and aOR, 36.50; 95% CI, 4.47–298.11, respectively). When implementing residual embolic fragments or stenosis at the thrombectomy site into the logistic regression model, discrimination between patients with and without reocclusion improved significantly (area under the curve, 0.955 versus 0.854;
P
=0.023). Early reocclusion was an independent predictor of unfavorable outcome at 90 days (aOR for modified Rankin Scale ≤2, 0.13; 95% CI, 0.03–0.57).

Conclusions—
Early reocclusion within 48 hours after successful mechanical thrombectomy is rare but associated with poor outcome. Patients with high platelets on admission and residual embolic fragments or stenosis at the thrombectomy site are at high risk for reocclusion, which may be prevented or corrected after carefully re-evaluating the last angiographic run.