bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Movement Patterns and Body Composition of High-Level Volleyball, Soccer, and Rugby Players
Authors: Campa Francesco , Piras Alessandro , Raffi Milena , Toselli Stefania
Published: September 2018

Context: Sports practice leads athletes to develop a specific body composition, coordination patterns, and basic motor skills based on the different tactical and physical needs. Objectives: To present and compare a wide range of functional movement patterns and body composition (BC) parameters of high-level male athletes playing different sports and to determine if there was a relationship between the parameters examined. Design: Cross-sectional study. Setting: Team facilities. Participants: A total of 30 volleyball, 25 soccer, and 30 rugby players (age = 25.9 [5.0] y and body mass index = 25.6 [4.1] kg/m2). Interventions: Functional movement patterns and anthropometric measurements were collected by a physician specifically trained. Main Outcome Measures: Body mass index, fat mass, fat-free mass, upper-arm muscle and fat area, calf muscle and fat area, thigh muscle and fat area, and functional movement screen (FMS) scores. In addition to considering the FMS total score, the authors separated the screen into 3 parts: FMSmove, FMSflex, and FMSstab. Results: The rugby players showed a higher number of asymmetrical and dysfunctional movements than the other athletes (P < .01), while the highest scores in FMSflex were obtained by the volleyball players (P < .01). In addition, most of the asymmetrical and painful movements in the athletes were measured on the shoulder mobility test. Muscle and fat areas differed significantly among the athletes (P < .05). Significant associations were found between movement patterns and several BC variables. In particular, large negative correlations were measured between percentage of fat mass (r = −.616; P < .01), upper-arm fat area (r = −.519; P < .01), and FMS total score. Conclusions: Functional movement patterns and BC differ in athletes according to the sport practiced. Furthermore, reaching an optimal BC is essential to achieve a satisfactory quality of movement.
Effect of Lower Limb Muscle Fatigue on Ground Reaction Force Components During Landing in People With Nonspecific Chronic Low Back Pain
Authors: Jalalvand Ali , Anbarian Mehrdad
Published: September 2018

Context: The link between landing parameters and lower limb muscle fatigue in association with chronic low back pain (CLBP) is not well understood. Objective: To examine the effects of fatigue on the ground reaction force components during landing in people with nonspecific CLBP. Design: Quasi-experimental study. Setting: Clinical biomechanics laboratory. Participants: A total of 44 subjects were equally divided into a healthy group and a group with CLBP. Main Outcome Measures: The ground reaction force along anterior–posterior (y) and medial–lateral (x) and vertical (z) axes, time to peak (TTP), the rate of force development, and impulses for all axes were calculated. A repeated-measures analysis of variance (group × fatigue) was used to compare the data among groups. Results: In the unfatigued conditions, the amplitudes of Fy3, Fz2, and TTP of Fy1, Fy2, Fz1, Fz2, Fz3, Fz4, rate of force development in Y in the CLBP subjects are significantly different than those in the healthy subjects (P < .05). In the fatigued conditions, the amplitudes of Fz2, Fz3, Fz4, and TTP of Fy2, Fy3, Fy4, Fz2, impulses of X2, Z in the CLBP group were significantly different than those in the healthy subjects (P < .05). Within-group comparisons of measured Fx1, Fy1, Fy2, Fz2, Fz4 and TTP of Fx1, Fy1, Fy2, Fz2, Fz3, Fz4, impulses of X2, z were significantly different from prefatigue to postfatigue in the healthy group (P < .05). Within-group comparisons of measured Fx1, Fy1, Fz1, Fz2 and TTP of Fx5, Fz1, impulses of X2 were significantly differed from prefatigue to postfatigue in the CLBP group (P < .05). Conclusions: It seems that TTP of ground reaction force variables in CLBP may have clinical values for rehabilitation. Muscle fatigue altered landing performance. However, patients with CLBP will respond differently to lower-extremity fatigue. These altered variables in patients with low back pain are the cause of future injuries or lower-extremity injuries that need to be addressed in further studies.
Antimicrobial Susceptibility of Pseudomonas aeruginosa to Ceftazidime-Avibactam, Ceftolozane-Tazobactam, Piperacillin-Tazobactam, and Meropenem Stratified by U.S. Census Divisions: Results from the 2017 INFORM Program
Authors: Sader Helio S. , Flamm Robert K. , Carvalhaes Cecilia G. , Castanheira Mariana
Published: September 2018

Pseudomonas aeruginosa
isolates (
n
= 1,909) were collected from 70 U.S. medical centers, and their susceptibilities were tested using the broth microdilution method.
Chronic Airway Colonization by Achromobacter xylosoxidans in Cystic Fibrosis Patients Is Not Sustained by Their Domestic Environment
Authors: Dupont Chloé , Jumas-Bilak Estelle , Doisy Clara , Aujoulat Fabien , Chiron Raphaël , Marchandin Hélène
Published: September 2018

Achromobacter
spp. are worldwide emerging opportunistic pathogens in CF patients, able to chronically colonize the respiratory tract. Apart from regular consultations at the hospital CF center, patients spend most of their time at home. Colonization from nonhuman sources has been suggested, but the presence of
Achromobacter
spp. in CF patients' homes has not been explored. The domestic environments of CF patients chronically colonized by
Achromobacter
, especially wet environments, host several opportunistic pathogens, including a large diversity of
Achromobacter
species and genotypes. However,
Achromobacter
genotypes colonizing the patients were not detected in their domestic environments, making it unlikely that a shuttle between environment and CF airways is involved in persisting colonization. This also suggests that once the bacteria have adapted to the respiratory tract, their survival in the domestic environment is presumably impaired. Nevertheless, measures for reducing domestic patient exposure should be targeted on evacuation drains, which are frequently contaminated by CF opportunistic pathogens.
Modulation of CrbS-Dependent Activation of the Acetate Switch in Vibrio cholerae
Authors: Muzhingi Itai , Prado Cecilia , Sylla Mariame , Diehl Frances F. , Nguyen Duy K. , Servos Mariah M. , Flores Ramos Stephany , Purdy Alexandra E.
Published: September 2018

CrbS is a member of a unique family of sensor histidine kinases, as its structure suggests that it may link signaling to the transport of a molecule. However, mechanisms through which CrbS senses and communicates information about the outside world are unknown. In the
Vibrionaceae
, orthologs of CrbS regulate acetate metabolism, which can, in turn, affect interactions with host organisms. Here, we situate CrbS within a larger regulatory framework, demonstrating that
crbS
is regulated by nutrient-sensing systems. Furthermore, CrbS domains may play various roles in signaling during infection and growth in culture, suggesting a unique mechanism of host recognition. Finally, we define the roles of additional pathways in acetate flux, as a foundation for further studies of this metabolic nexus point.
Classifying atopic dermatitis: protocol for a systematic review of subtypes (phenotypes) and associated characteristics
Authors: Mulick Amy R , Allen Victoria , Williams Hywel C , Grindlay Douglas J C , Pearce Neil , Abuabara Katrina , Langan Sinéad M
Published: September 2018

Introduction

Atopic dermatitis is a complex disease with differing clinical presentations. Many attempts have been made to identify uniform subtypes, or phenotypes, of atopic dermatitis in order to identify different aetiologies, improve diagnosis, estimate more accurate clinical prognoses, inform treatment andmanagement or predict treatment efficacy andeffectiveness. However, no consensus yet exists on exactly what defines these phenotypes or how many there are and whether they are genuine or statistical artefacts. This review aims to identify previously reported phenotypes of atopic dermatitis, the features used to define them and any characteristics or clinical outcomes significantly associated with them.

Methods and analysis

We will search Ovid Embase, Ovid MEDLINE and Web of Science from inception to the latest available date at the time of the search for studies attempting to classify atopic dermatitis in humans using any cross-sectional or longitudinal epidemiological or interventional design. Primary outcomes are atopic dermatitis phenotypes, features used to define them and characteristics associated with them in subsequent analyses. A secondary outcome is the methodological approach used to derive them. Two reviewers will independently screen titles and abstracts for inclusion, extract data and assess study quality. We will present the results of this review descriptively and with frequencies where possible.

Ethics and dissemination

Ethical approval is not required for this study as it is a systematic review. We will report results from this systematic review in a peer-reviewed journal. The main value of this study will be to inform further research.

PROSPERO registration number

CRD42018087500
Policy addressing suicidality in children and young people: a scoping review protocol
Authors: Gilmour Lynne , Duncan Edward , Maxwell Margaret
Published: September 2018

Introduction

Suicide is one of the leading causes of death among children and young people globally and a major public health issue. Government policies determine how much recognised health issues are prioritised and set the context for investment, development and delivery of services. A review of policies concerning children and young people who are suicidal could shed light on the extent that this public health issue is prioritised and highlight examples of best practice in this area. There has never been a review to explore how policy worldwide addresses the specific needs of this vulnerable population. This review will map the key policy documents and identify their relevance to the review question: how does policy address the treatment and care of children and young people who experience suicidality? (international, national (UK) and local (Scotland)).

Methodology

Employing scoping review methodological guidance a systematic and transparent approach will be taken. Preliminary searches will facilitate the identification of MeSh terms, subject headings, individual database and platform nuances. A full search strategy will be created to search five databases: CINAHL, PsychInfo, Medline, Web of Science and Cochrane. Government and other key agency websites (eg, WHO, Unicef) will be searched to identify policy documents. The reference lists of identified documents will be checked. A second reviewer will independently screen and cross validate eligible studies for final inclusion. A data extraction template will then be used to extract key information. We will report our findings using narrative synthesis and tabulate findings, by agreed key components.

Ethics and dissemination

Ethical approval is not required to conduct a scoping review. We will disseminate the findings through a peer-reviewed publication and conference presentation.
Essential fracture and orthopaedic equipment lists in low resource settings: consensus derived by survey of experts in Africa
Authors: Chan Yuen , Banza Leonard , Martin Jr Claude , Harrison William J
Published: September 2018

Introduction

Low/middle-income countries (LMICs) have a growing need for trauma and orthopaedic (T&O) surgical interventions but lack surgical resources. Part of this is due to the high amount of road traffic accidents in LMICs. We aimed to develop recommendations for an essential list of equipment for three different levels of care providers.

Methods

The Delphi method was used to achieve consensus on essential and desirable T&O equipment for LMICs. Twenty experts with T&O experience from LMICs underwent two rounds of questionnaires. Feedback was given after each round of questionnaires. The first round of questionnaire consisted of 45 items graded on a Likert scale with the second round consisting of 50 items. We used an electronic questionnaire to collect our data for three different levels of care: non-operative-based provider, specialist provider with operative fracture care and tertiary provider with operative fracture care and orthopaedics.

Results

After two rounds of questionnaires, recommendations for each level of care in LMICs included 4 essential equipment items for non-operative-based providers; 27 essential equipment items for specialist providers with operative fracture care and 46 essential equipment items for tertiary providers with operative fracture care and orthopaedic care.

Conclusion

These recommendations can facilitate in planning of appropriate equipment required in an institution which in turn has the potential to improve the capacity and quality of T&O care in LMICs. The essential equipment lists provided here can help direct where funding for equipment should be targeted. Our recommendations can help with planning and organising national T&O care in LMICs to achieve appropriate capacity at all relevant levels of care.
Presenting a strong and united front to tobacco industry interference : a content analysis of Australian newspaper coverage of tobacco plain packaging 2008–2014
Authors: Miller Caroline Louise , Brownbill Aimee Lee , Dono Joanne , Ettridge Kerry
Published: September 2018

Objectives

In 2012, Australia was the first country in the world to introduce plain or standardised tobacco packaging, coupled with larger graphic health warnings. This policy was fiercely opposed by industry. Media coverage can be an influential contributor to public debate, and both public health advocates and industry sought media coverage for their positions. The aim of this study was to measure the print media coverage of Australian’s plain packaging laws, from inception to roll-out, in major Australian newspapers.

Methods

This study monitored mainstream Australian print media (17 newspapers) coverage of the plain packaging policy debate and implementation, over a 7-year period from January 2008 to December 2014. Articles (n=701) were coded for article type, opinion slant and topic(s).

Design

Content analysis.

Results

Coverage of plain packaging was low during preimplementation phase (2008–2009), increasing sharply in the lead into legislative processes and diminished substantially after implementation. Articles covered policy rationale, policy progress and industry arguments. Of the news articles, 96% were neutrally framed. Of the editorials, 55% were supportive, 28% were opposing, 12% were neutral and 5% were mixed.

Conclusions

Protracted political debate, reflected in the media, led to an implementation delay of plain packaging. While Australian media provided comprehensive coverage of industry arguments, news coverage was largely neutral, whereas editorials were mostly supportive or neutral of the policy. Countries seeking to implement plain packaging of tobacco should not be deterred by the volume of news coverage, but should actively promote the evidence for plain packaging in the media to counteract the arguments of the tobacco industry.
Curricula and methods for physician compassion training: protocol for a systematic review
Authors: Patel Sundip , Pelletier-Bui Alexis , Smith Stephanie , Roberts Michael B , Kilgannon Hope J , Trzeciak Stephen , Roberts Brian W
Published: September 2018

Introduction

Compassionate patient care has been associated with improved clinical outcomes for patients. However, current evidence suggests that healthcare is experiencing a compassion crisis, with physicians frequently overlooking opportunities to treat patients with compassion. Although there is evidence that compassionate care can be enhanced through training interventions, it is currently unclear what specific skills and behaviours ought to be taught and how best to transfer this information to the learner. The objectives of this systematic review are to collate the world’s literature on compassion training to determine (1) the specific skills and behaviours that should be taught (curriculum), and (2) the methods of training that are most effective at improving compassionate patient care.

Methods and analysis

We will perform a qualitative systematic review of studies aimed at improving compassionate patient care among physicians and physicians in training. We will comprehensively search CENTRAL, MEDLINE, EMBASE and CINAHL. Additional recommended techniques for systematic reviews of complex evidence will be performed including pursuing selected ‘references of references’, electronic citation tracking and consulting experts in the field. Two investigators will independently review all search results. After identification and inclusion of papers, we will use a standardised form for data extraction. We will use tables to describe the study populations, interventions tested (including specific skill/behaviours taught and training methods used), outcome measures and effects of interventions on outcome measures compared with control groups. Where appropriate, meta-analysis will be used for quantitative analysis of the data.

Ethics and dissemination

The proposed systematic review does not require ethical approval since no individual patient-level data will be collected. Results of this study will contribute to the understanding of compassion training and help inform the development of compassion training curricula.

PROSPERO registration number

CRD42018095040.
Forced air warming during sedation in the cardiac catheterisation laboratory: a randomised controlled trial
Authors: Conway Aaron , Ersotelos Suzanna , Sutherland Joanna , Duff Jed
Published: September 2018

Objective

Forced air warming (FAW) during general anaesthesia is a safe and effective intervention used to reduce hypothermia. The objective of this study was to determine if FAW reduces hypothermia when used for procedures performed with sedation in the cardiac catheterisation laboratory.

Methods

A parallel-group randomised controlled trial was conducted. Adults receiving sedation in a cardiac catheterisation laboratory at two sites were randomised to receive FAW or usual care, which involved passive warming with heated cotton blankets. Hypothermia, defined as a temperature less than 36°C measured with a sublingual digital thermometer after procedures, was the primary outcome. Other outcomes were postprocedure temperature, shivering, thermal comfort and major complications.

Results

A total of 140 participants were randomised. Fewer participants who received FAW were hypothermic (39/70, 56% vs 48/69, 70%, difference 14%; adjusted RR 0.75, 95% CI=0.60 to 0.94), and body temperature was 0.3°C higher (95% CI=0.1 to 0.5, p=0.004). FAW increased thermal comfort (63/70, 90% vs51/69, 74% difference 16%, RR 1.21, 95% CI=1.04 to 1.42). The incidence of shivering was similar (3/69, 4% vs 0/71 0%, difference 4%, 95% CI=−1.1 to 9.8). One patient in the control group required reintervention for bleeding. No other major complications occurred.

Conclusion

FAW reduced hypothermia and improved thermal comfort. The difference in temperature between groups was modest and less than that observed in previous studies where use of FAW decreased risk of surgical complications. Therefore, it should not be considered clinically significant.

Trial registration number

ACTRN12616000013460.
Medical Use of Sensor-Based Devices, the Debates Around and Implementation in Education
Authors: Adiguzel Yekbun , Valdez Kristel P. Ramirez , Yurur Gulkizilca
Published: September 2018

Sensor-based diagnostics are increasing rapidly and in clinics, they can transform the health care as they will be in use out of clinics as well, namely, by the non-clinicians and people without expertise. The trade-off between the advantages and disadvantages of their implementation into the clinical settings should be decisive in their use, at the current state. Yet, disadvantages must be carefully worked out and tried to be eliminated in any case, while keeping the inborn benefits. Therefore, we would like to draw attention to the reliability and security risks of personal health data and associated concerns. We further discuss the related issues of sensor-based diagnostics, mobile health (mHealth) and eHealth. The debate starts with the current states of the rules and regulations. It is argued that there is prompt need for internationally consolidated solutions for vast device types and uses onto which the local needs may have to be implemented without violating the basic assets such as the inherent privacy rights of the users/patients. The resistance factors against the sensor-based healthcare devices and applications are also conferred. There are additionally data quality and assessment issues, and in relation to the data assessment, concerns that are associated with the psychological responses of the layman to the health data are mentioned. For these and more reasons, and finally for proper use and implementation of sensor-based tests and devices in the clinical settings, education of both professionals and non-professionals seems to be the key. All these require much work and maybe even more workforces to be allocated for the emerging, associated tasks. However, there are economic benefits, and beyond those, they bring new features in the health care that were deemed to be impossible. Besides, despite the apparent unethical use risks, they can result in better ethical practices, e.g., possible prevention of unnecessary tests on animals when similar test on organ-on-chips would be failing.
Uniqueness, Spatial Mixing, and Approximation for Ferromagnetic 2-Spin Systems
Authors: Guo Heng , Lu Pinyan
Published: September 2018

We give fully polynomial-time approximation schemes (FPTAS) for the partition function of ferromagnetic 2-spin systems in certain parameter regimes. The threshold we obtain is almost tight up to an integrality gap. Our technique is based on the correlation decay framework. The main technical contribution is a new potential function, with which we establish a new kind of spatial mixing.
Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers
Authors: Elion David L. , Jacobson Max E. , Hicks Donna J. , Rahman Bushra , Sanchez Violeta , Gonzales-Ericsson Paula I. , Fedorova Olga , Pyle Anna M. , Wilson John T. , Cook Rebecca S.
Published: September 2018

Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum but have not achieved widespread success in breast cancers, a tumor type considered poorly immunogenic and which harbors a decreased presence of tumor-infiltrating lymphocytes. Approaches that activate innate immunity in breast cancer cells and the tumor microenvironment are of increasing interest, based on their ability to induce immunogenic tumor cell death, type I IFNs, and lymphocyte-recruiting chemokines. In agreement with reports in other cancers, we observe loss, downregulation, or mutation of the innate viral nucleotide sensor retinoic acid-inducible gene I (RIG-I/DDX58) in only 1% of clinical breast cancers, suggesting potentially widespread applicability for therapeutic RIG-I agonists that activate innate immunity. This was tested using an engineered RIG-I agonist in a breast cancer cell panel representing each of three major clinical breast cancer subtypes. Treatment with RIG-I agonist resulted in upregulation and mitochondrial localization of RIG-I and activation of proinflammatory transcription factors STAT1 and NF-κB. RIG-I agonist triggered the extrinsic apoptosis pathway and pyroptosis, a highly immunogenic form of cell death in breast cancer cells. RIG-I agonist also induced expression of lymphocyte-recruiting chemokines and type I IFN, confirming that cell death and cytokine modulation occur in a tumor cell–intrinsic manner. Importantly, RIG-I activation in breast tumors increased tumor lymphocytes and decreased tumor growth and metastasis. Overall, these findings demonstrate successful therapeutic delivery of a synthetic RIG-I agonist to induce tumor cell killing and to modulate the tumor microenvironment in vivo.

Significance: These findings describe the first in vivo delivery of RIG-I mimetics to tumors, demonstrating a potent immunogenic and therapeutic effect in the context of otherwise poorly immunogenic breast cancers. Cancer Res; 78(21); 6183–95. ©2018 AACR.
Activation of B-1 Cells Promotes Tumor Cell Killing in the Peritoneal Cavity
Authors: Haro Marcela A. , Dyevoich Allison M. , Phipps James P. , Haas Karen M.
Published: September 2018

Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Activating the antitumor immune response in the characteristically immune-suppressive peritoneal environment presents a potential strategy to treat this disease. In this study, we show that a toll-like receptor (TLR) and C-type lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6′-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development in a mouse model of aggressive mammary cancer–induced peritoneal carcinomatosis. MPL/TDCM treatment similarly inhibited peritoneal EL4 tumor growth and ascites development. These effects were not observed in mice lacking B cells or mice lacking CD19, which are deficient in B-1a cells, an innate-like B-cell population enriched in the peritoneal cavity. Remarkably, adoptive transfer of B-1a cells, but not splenic B cells from WT mice, restored MPL/TDCM-induced protection in mice with B-cell defects. Treatment induced B-1 cells to rapidly produce high levels of natural IgM reactive against tumor-associated carbohydrate antigens. Consistent with this, we found significant deposition of IgM and C3 on peritoneal tumor cells as early as 5 days post-treatment. Mice unable to secrete IgM or complement component C4 were not protected by MPL/TDCM treatment, indicating tumor killing was mediated by activation of the classical complement pathway. Collectively, our findings reveal an unsuspected role for B-1 cell–produced natural IgM in providing protection against tumor growth in the peritoneal cavity, thereby highlighting potential opportunities to develop novel therapeutic strategies for the prevention and treatment of peritoneal metastases.

Significance:

This work identifies a critical antitumor role for innate-like B cells localized within the peritoneal cavity and demonstrates a novel strategy to activate their tumor-killing potential.

See related commentary by Tripodo, p. 5
UBE2N Promotes Melanoma Growth via MEK/FRA1/SOX10 Signaling
Authors: Dikshit Anushka , Jin Yingai J. , Degan Simone , Hwang Jihwan , Foster Matthew W. , Li Chuan-Yuan , Zhang Jennifer Y.
Published: September 2018

UBE2N is a K63-specific ubiquitin conjugase linked to various immune disorders and cancer. Here, we demonstrate that UBE2N and its partners UBE2V1 and UBE2V2 are highly expressed in malignant melanoma. Silencing of UBE2N and its partners significantly decreased melanoma cell proliferation and subcutaneous tumor growth. This was accompanied by increased expression of E-cadherin, p16, and MC1R and decreased expression of melanoma malignancy markers including SOX10, Nestin, and ABCB5. Mass spectrometry–based phosphoproteomic analysis revealed that UBE2N loss resulted in distinct alterations to the signaling landscape: MEK/ERK signaling was impaired, FRA1 and SOX10 gene regulators were downregulated, and p53 and p16 tumor suppressors were upregulated. Similar to inhibition of UBE2N and MEK, silencing FRA1 decreased SOX10 expression and cell proliferation. Conversely, exogenous expression of active FRA1 increased pMEK and SOX10 expression, and restored anchorage-independent cell growth of cells with UBE2N loss. Systemic delivery of NSC697923, a small-molecule inhibitor of UBE2N, significantly decreased melanoma xenograft growth. These data indicate that UBE2N is a novel regulator of the MEK/FRA1/SOX10 signaling cascade and is indispensable for malignant melanoma growth. Our findings establish the basis for targeting UBE2N as a potential treatment strategy for melanoma.

Significance: These findings identify ubiquitin conjugase UBE2N and its variant partners as novel regulators of MAPK signaling and potential therapeutic targets in melanoma. Cancer Res; 78(22); 6462–72. ©2018 AACR.
Tracking Cell Transplants in Femoral Osteonecrosis with Magnetic Resonance Imaging: A Proof-of-Concept Study in Patients
Authors: Theruvath Ashok J. , Nejadnik Hossein , Muehe Anne M. , Gassert Felix , Lacayo Norman J. , Goodman Stuart B. , Daldrup-Link Heike E.
Published: September 2018

Purpose:

Osteonecrosis is a devastating complication of high-dose corticosteroid therapy in patients with cancer. Core decompression for prevention of bone collapse has been recently combined with the delivery of autologous concentrated bone marrow aspirates. The purpose of our study was to develop an imaging test for the detection of transplanted bone marrow cells in osteonecrosis lesions.

Experimental Design:

In a prospective proof-of-concept clinical trial (NCT02893293), we performed serial MRI studies of nine hip joints of 7 patients with osteonecrosis before and after core decompression. Twenty-four to 48 hours prior to the surgery, we injected ferumoxytol nanoparticles intravenously to label cells in normal bone marrow with iron oxides. During the surgery, iron-labeled bone marrow cells were aspirated from the iliac crest, concentrated, and then injected into the decompression track. Following surgery, patients received follow-up MRI up to 6 months after bone marrow cell transplantation.

Results:

Iron-labeled cells could be detected in the access canal by a dark (negative) signal on T2-weighted MR images. T2* relaxation times of iron-labeled cell transplants were significantly lower compared with unlabeled cell transplants of control patients who were not injected with ferumoxytol (P = 0.02). Clinical outcomes of patients who received ferumoxytol-labeled or unlabeled cell transplants were not significantly different (P = 1), suggesting that the added ferumoxytol administration did not negatively affect bone repair.

Conclusions:

This immediately clinically applicable imaging test could become a powerful new tool to monitor the effect of therapeutic cells on bone repair outcomes after corticosteroid-induced osteonecrosis.
USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia
Authors: Jin Qi , Martinez Carlos A. , Arcipowski Kelly M. , Zhu Yixing , Gutierrez-Diaz Blanca T. , Wang Kenneth K. , Johnson Megan R. , Volk Andrew G. , Wang Feng , Wu Jian , Grove Charles , Wang Hui , Sokirniy Ivan , Thomas Paul M. , Goo Young Ah , Abshiru Nebiyu A. , Hijiya Nobuko , Peirs Sofie , Vandamme Niels , Berx Geert , Goosens Steven , Marshall Stacy A. , Rendleman Emily J. , Takahashi Yoh-hei , Wang Lu , Rawat Radhika , Bartom Elizabeth T. , Collings Clayton K. , Van Vlierberghe Pieter , Strikoudis Alexandros , Kelly Stephen , Ueberheide Beatrix , Mantis Christine , Kandela Irawati , Bourquin Jean-Pierre , Bornhauser Beat , Serafin Valentina , Bresolin Silvia , Paganin Maddalena , Accordi Benedetta , Basso Giuseppe , Kelleher Neil L. , Weinstock Joseph , Kumar Suresh , Crispino John D. , Shilatifard Ali , Ntziachristos Panagiotis
Published: September 2018

Purpose:

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes.

Experimental Design:

To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models.

Results:

We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo.

Conclusions:

These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.
p53 Function Is Compromised by Inhibitor 2 of Phosphatase 2A in Sonic Hedgehog Medulloblastoma
Authors: Wei Yun , Maximov Victor , Morrissy Sorana A. , Taylor Michael D. , Pallas David C. , Kenney Anna Marie
Published: September 2018

Medulloblastomas, the most common malignant pediatric brain tumors, have been genetically defined into four subclasses, namely WNT-activated, Sonic Hedgehog (SHH)-activated, Group 3, and Group 4. Approximately 30% of medulloblastomas have aberrant SHH signaling and thus are referred to as SHH-activated medulloblastoma. The tumor suppressor gene TP53 has been recently recognized as a prognostic marker for patients with SHH-activated medulloblastoma; patients with mutant TP53 have a significantly worse outcome than those with wild-type TP53. It remains unknown whether p53 activity is impaired in SHH-activated, wild-type TP53 medulloblastoma, which is about 80% of the SHH-activated medulloblastomas. Utilizing the homozygous NeuroD2:SmoA1 mouse model with wild-type Trp53, which recapitulates human SHH-activated medulloblastoma, it was discovered that the endogenous Inhibitor 2 of Protein Phosphatase 2A (SET/I2PP2A) suppresses p53 function by promoting accumulation of phospho-MDM2 (S166), an active form of MDM2 that negatively regulates p53. Knockdown of I2PP2A in SmoA1 primary medulloblastoma cells reduced viability and proliferation in a p53-dependent manner, indicating the oncogenic role of I2PP2A. Importantly, this mechanism is conserved in the human medulloblastoma cell line ONS76 with wild-type TP53. Taken together, these findings indicate that p53 activity is inhibited by I2PP2A upstream of PP2A in SHH-activated and TP53-wildtype medulloblastomas.

Implications:

This study suggests that I2PP2A represents a novel therapeutic option and its targeting could improve the effectiveness of current therapeutic regimens for SHH-activated or other subclasses of medulloblastoma with wild-type TP53.
Sterile Inflammatory Role of High Mobility Group Box 1 Protein: Biological Functions and Involvement in Disease
Authors: Gonelevue Sera , Bandyopadhyay Abhirup , Bhagat Saumya , Alam Md Iqbal , Khan Gausal A.
Published: September 2018

High mobility group box 1 protein (HMGB1), a sterile inflammatory molecule and damage-associated molecular pattern (DAMP) released from various cells during stress has been implicated in inflammation. Several reports show that there is a direct relationship between inflammation and cardiovascular diseases (CVDs) such as thrombosis, hypertension, insulin resistance, preeclampsia, etc. Here, we intend to summarize the concept of the emerging link between HMGB1 and CVDs. Furthermore, we will discuss the possible therapeutic strategies that target HMGB1 for the treatment of different CVDs.
The Recurrence Risk of Fetomaternal Hemorrhage
Authors: Troìa Libera , Al-Kouatly Huda B. , McCurdy Rebekah , Konchak Peter S. , Weiner Stuart , Berghella Vincenzo
Published: September 2018

Massive fetomaternal hemorrhage (FMH) can cause devastating pregnancy outcomes. Perinatal prognosis may be improved by intrauterine transfusion, but the appropriate management for these pregnancies remains unclear. To determine the recurrence risk of FMH after intrauterine transfusion, we performed a systematic review of all case reports/series of patients with proven FMH treated with intrauterine transfusion and who had subsequent follow-up of at least 72 h until delivery. This revealed 13 cases, with 1 additional case from our institution. Ten patients (71.4%) had a second episode of FMH requiring a second intrauterine transfusion. Five patients (35.7%) required at least 3 intrauterine transfusions. The time interval between intrauterine transfusions was progressively reduced. The gestational age at the onset of signs/symptoms was 26.6 ± 2.1 weeks, and gestational age at delivery was 34.2 ± 4.2 weeks. Two cases of fetal demise (14.3%) and no neonatal deaths were recorded. Limited postnatal follow-up on 8 neonates was normal. The mean neonatal hemoglobin and transfusion rates were 13.2 ± 5.7 g/dL and 33.3%, respectively. Close fetal monitoring, likely daily, is necessary to recognize FMH recurrence. Several transfusions may be necessary once FMH is diagnosed if pregnancy is allowed to continue > 72 h.
Proliferation Potential-Related Protein Promotes the Esophageal Cancer Cell Proliferation, Migration and Suppresses Apoptosis by Mediating the Expression of p53 and Interleukin-17
Authors: Ye Fei , Song Jizhong , Wang Yetao , Xu Xuemei , Zhang Kaiguang
Published: September 2018

Objective: This study aims to investigate the mechanism of proliferation potential-related protein (PP-RP) in influencing the proliferation, migration, and apoptosis of esophageal cancer cells. Methods: Quantitative real-time PCR and western blotting were performed to analyze the expression of PP-RP gene, p53, and interleukin (IL)-17 in human normal tissues and tumor tissues, as well as the expression of p53 and IL-17 in Eca109 and TE3 cells. The esophageal cancer cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cell apoptosis was detected by flow cytometry, and cell migration was detected by transwell migration. Results: PP-RP expressed highly in tumor tissue and Eca109 and TE3 cells, PP-RP overexpression inhibited the expression of p53 and promoted the expression of IL-17 in Eca109 and TE3 cells. PP-RP overexpression increased the expression of F-actin, promoted cell proliferation, and migration and suppressed cell apoptosis. Cell proliferation ability and cell migration ability were significantly strengthened while apoptosis was suppressed by PP-RP + pyruvate carboxylase deoxyribonucleic acid (PCDNA)-p53 group and PP-RP + IL-17 siRNA group in TE3 cells. Conclusion: Our data suggest that PP-RP promotes esophageal cancer cell proliferation and migration, and suppresses apoptosis by mediating the expression of p53 and IL-17.
Annual Incidence and Phenotypic Presentation of IBD in Southern New Zealand: An 18-Year Epidemiological Analysis
Authors: Coppell Kirsten J. , Galts Ciarán P.-C. , Huizing Fokko Y. , Norton Joanna K. , Gray Andrew R. , Schultz Kim , Hobbs Catherine E. , Aluzaite Kristina , Schultz Michael
Published: September 2018

Background: The aim of this study was to describe the incidence of inflammatory bowel disease (IBD) and changes in demographic and phenotypic disease presentation in Otago, New Zealand. Methods: This study was conducted at Dunedin Hospital and the study period was 1996–2013. Otago residents diagnosed with IBD were identified retrospectively from hospital lists using ICD-10 codes. Diagnosis, and place and date of diagnosis, were confirmed using medical notes and histology reports. Demographic, clinical and diagnostic data were recorded. Age-standardised incidence rates were estimated and trends over time assessed. Multinomial logistic regression was used to assess evidence for any changes in the distribution of disease location for Crohn’s disease (CD) cases. Results: The diagnosis of IBD was confirmed in 224 males and 218 females, and most were New Zealand European. Of the total number of confirmed IBD cases, 40.0% were ulcerative colitis (UC), 52.1% were CD and 7.9% were IBD unclassified. The age distribution illustrated bimodal peaks at 20–24 years and 65–69 years. Incidence rates varied from year to year, but there was no statistically significant change over the 18-year study period. The estimated age-standardised IBD incidence varied between 5.8/100,000 in 2006 and 29.8/100,000 in 2012. The incidence rates for UC and CD were 2.8/100,000 and 1.8/100,000, respectively, in 2006 and 6.3/100,000 and 21.8/100,000, respectively, in 2012. There were no significant phenotypic changes in CD patients over the study period. Conclusions: The IBD incidence in Otago, New Zealand, is high compared to many other countries. Annual age-standardised incidence rates vary, highlighting the limitations of single-year incidence data.
The Importance of Adherence in the Treatment of Secondary Hyperparathyroidism
Authors: Alfieri Carlo , Regalia Anna , Zanoni Francesca , Vettoretti Simone , Cozzolino Mario , Messa Piergiorgio
Published: September 2018

Secondary hyperparathyroidism (SHPT) is a frequent condition in the presence of chronic kidney disease (CKD). In CKD patients, SHPT is reported to increase both morbidity and mortality, especially cardiovascular. The difficulty in the treatment of SHPT in clinical practice is frequently encountered from a not always adequate conduct of the clinicians and a common non-compliance to the therapy of CKD patients. In this review, the greatest difficulties from clinicians and CKD-patients’ point of view in the treatment of SHPT will be addressed, with particular attention to those related to dialysis features, nutritional habits, and medical therapy.
Prospective, Tissue-Specific Optimization of Ablation for Multiwavelet Reentry
Authors: Carrick Richard T. , Benson Bryce E. , Bates Jason H.T. , Spector Peter S.
Published: September 2018

Background—

Treatment of multiwavelet reentry (MWR) remains difficult. We previously developed a metric, the fibrillogenicity index, to assess the propensity of homogeneous, 2-dimensional tissues to support MWR. In this study, we demonstrate a method by which fibrillogenicity index can be generalized to heterogeneous tissues and validate an algorithm for prospective, tissue-specific optimization of ablation to reduce MWR burden.

Methods and Results—

We used a computational model to simulate and measure the duration of MWR in tissues with heterogeneously distributed action potential durations and then assessed the relative efficacy of a variety of ablation strategies for reducing tissues’ ability to support MWR. We then derived and tested a strategy in which multiple linear lesions partially divided a fibrillogenic tissue into functionally equivalent subsections. The composite action potential duration of heterogeneous tissue was well approximated by an inverse sum of cellular action potential durations (
R
2
=0.82). Linear ablation more efficiently reduced MWR duration than branching ablation patterns and optimally reduced disease burden when positioned at a tissue’s functional (rather than geometric) center. The duration of MWR after application of prospective, individually optimized ablation sets fell within 4.4% (95% confidence interval, 3–5.8) of the predicted target.

Conclusions—

We think that this study presents a novel approach for (1) quantifying the extent of a tissue’s electric derangement, (2) prospectively determining the amount of ablation required to minimize the burden of MWR, and (3) predicting the most efficient distribution of these ablation lesions in tissue refractory to standard ablation strategies.
Relation of Left Ventricular Mass to Prognosis in Initially Asymptomatic Mild to Moderate Aortic Valve Stenosis
Authors: Gerdts Eva , Rossebø Anne B. , Pedersen Terje R. , Cioffi Giovanni , Lønnebakken Mai Tone , Cramariuc Dana , Rogge Barbara P. , Devereux Richard B.
Published: September 2018

Background—

The prognostic importance of left ventricular (LV) mass in nonsevere asymptomatic aortic stenosis has not been documented in a large prospective study.

Methods and Results—

Cox regression analysis was used to assess the impact of echocardiographic LV mass on rate of major cardiovascular events in 1656 patients (mean age, 67 years; 39.6% women) with mild-to-moderate asymptomatic aortic stenosis participating in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study. Patients were followed during 4.3 years of randomized treatment with combined simvastatin 40 mg and ezetimibe 10 mg daily or placebo. At baseline, LV mass index was 45.9
+
14.9 g/m
2.7
, and peak aortic jet velocity was 3.09
+
0.54 m/s. During follow-up, 558 major cardiovascular events occurred. In Cox regression analyses, 1 SD (15 g/m
2.7
) higher baseline LV mass index predicted increases in hazards of 12% for major cardiovascular events, 28% for ischemic cardiovascular events, 34% for cardiovascular mortality, and 23% for combined total mortality and hospitalization for heart failure (all
P
<0.01), independent of confounders. In time-varying models, taking the progressive increase in LV mass index during follow-up into account, 1 SD higher in-study LV mass index was consistently associated with 13% to 61% higher hazard for cardiovascular events (all
P
<0.01), independent of age, sex, body mass index, valvuloarterial impedance, LV ejection fraction and concentricity, and the presence of concomitant hypertension.

Conclusions—

Higher LV mass index is independently associated with increased cardiovascular morbidity and mortality during progression of aortic stenosis.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00092677.
G-Protein–Coupled Receptors in Heart Disease
Authors: Wang Jialu , Gareri Clarice , Rockman Howard A.
Published: September 2018

GPCRs (G-protein [guanine nucleotide-binding protein]–coupled receptors) play a central physiological role in the regulation of cardiac function in both health and disease and thus represent one of the largest class of surface receptors targeted by drugs. Several antagonists of GPCRs, such as βARs (β-adrenergic receptors) and Ang II (angiotensin II) receptors, are now considered standard of therapy for a wide range of cardiovascular disease, such as hypertension, coronary artery disease, and heart failure. Although the mechanism of action for GPCRs was thought to be largely worked out in the 80s and 90s, recent discoveries have brought to the fore new and previously unappreciated mechanisms for GPCR activation and subsequent downstream signaling. In this review, we focus on GPCRs most relevant to the cardiovascular system and discuss traditional components of GPCR signaling and highlight evolving concepts in the field, such as ligand bias, β-arrestin–mediated signaling, and conformational heterogeneity.