bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol for a systematic review on interventions for caregivers of persons with mild cognitive impairment and early dementia: does early stage intervention improve caregiver well-being and ability to provide care?
Authors: Bayly Melanie , Morgan Debra , Kosteniuk Julie , Elliot Valerie , Froehlich Chow Amanda , Peacock Shelley , McLean Allen , O’Connell Megan E 
Published: May 2019

IntroductionCaregivers of persons with dementia and mild cognitive impairment (MCI) are at risk of decreased well-being. While many interventions for caregivers exist, evidence is sparse regarding intervention timing and effectiveness at an early stage of cognitive decline. Our systematic review aims to answer the following questions: (1) Do interventions for caregivers of persons with early stage dementia or MCI affect their well-being and ability to provide care? (2) Are particular types of caregiver interventions most effective during early stage cognitive decline? (3) How does effectiveness differ when early and later interventions are directly compared? (4) Do effects of early stage caregiver intervention vary based on care recipient and caregiver characteristics (eg, sex, type of dementia)?Methods and analysisThe databases MEDLINE, EMBASE, PSYCINFO and CINAHL, as well as grey literature databases, will be searched for English language studies using search terms related to caregiver interventions and dementia/MCI. Abstracts and full texts will be screened by two independent reviewers; included studies must assess the effects of an intervention for caregivers of persons with early stage dementia or MCI on caregiver well-being or ability to provide care. Intervention, study and participant characteristics will be extracted by two independent reviewers, along with outcome data. Risk of bias will be assessed using the Cochrane risk of bias tool (for controlled trials with and without randomisation). Interventions will be grouped by type (eg, psychoeducational) and a narrative synthesis is planned due to expected heterogeneity, but a meta-analysis will be performed where possible. The Grading of Recommendations, Assessment, Development and Evaluations approach will be used to inform conclusions regarding the quality of evidence for each type of intervention.Ethics and disseminationFindings from this review will be disseminated via conferences and peer-reviewed publication, and a summary will be provided to the Alzheimer Society.PROSPERO registration numberCRD42018114960.
Incidence and prevalence of lumbar stress fracture in English County Cricket fast bowlers, association with bowling workload and seasonal variation
Authors: Alway Peter , Brooke-Wavell Katherine , Langley Ben , King Mark , Peirce Nicholas 
Published: May 2019

ObjectivesSince much of the previous epidemiological research into lumbar stress fracture was conducted, there has been a marked increase in the amount of cricket being played. The aims were to determine the incidence and prevalence of lumbar stress fracture in English County Cricket fast bowlers between 2010 and 2016, determine the association with match bowling workload and observe seasonal variation in workload and injury.MethodsLumbar stress fracture incidence and prevalence rates were calculated using new international methods for epidemiology in 368 professional English fast bowlers from 2010 to 2016. Workload variables were compared between lumbar stress fracture case and non-injured control groups, before entry in a logistic regression.ResultsFifty-seven lumbar stress fractures (mean age 22.81) were reported. Injury was most common in July and September. Match incidence was 0.16 lumbar stress fractures per 10 000 deliveries, annual incidence was 2.46 lumbar stress fractures per 100 fast bowlers and annual prevalence of lumbar stress fractures was 1.67% of squad days. Significant workload variables were observed between cases and controls. A peak 7-day workload of greater than 234 deliveries significantly increased the odds of sustaining a lumbar stress fracture 11-fold compared with bowling fewer than 197 deliveries.ConclusionLumbar stress fractures are common in young fast bowlers possibly due to immaturity of the lumbar spine. The condensed early and late-season schedule may be causing periods of overuse, resulting in an increase in incidence of lumbar stress fracture. Reduction of workload in young fast bowlers is needed to reduce incidence.
Peripheral artery disease and outcomes in patients with acute myocardial infarction
Authors: Attar Rubina , Wester Axel , Koul Sasha , Eggert Svend , Andell Pontus 
Published: May 2019

AimTo describe the population of patients with previously diagnosed peripheral artery disease (PAD) experiencing a myocardial infarction (MI) and to investigate 1-year major adverse cardiac events (MACE: all-cause mortality, reinfarction, stroke and heart failure hospitalisation) following MI.BackgroundMI patients with PAD constitute a high-risk population with adverse cardiac outcomes. Contemporary real-life data regarding the clinical characteristics of this patient population and clinical event rates following MI remain scarce.MethodsThis observational study included all MI patients presenting with ST-elevation MI or non-ST-elevation MI between 01 January 2005 and 31 December 2014 with (n=4213) and without (n=106 763) a concurrent PAD diagnosis, identified in the nationwide Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry and the National Patient Registry (PAD prevalence: 3.8%). Cox proportional hazard models were applied to compare the outcome between the two populations.ResultsMI patients with PAD were older and more often burdened with comorbidities, such as diabetes, hypertension and previous MI. After adjustments, PAD was significantly associated with higher rates of MACE (HR 1.35, 95% CI 1.27 to 1.44), mortality (HR 1.59, 95% CI 1.43 to 1.76), reinfarction (HR 1.48, 95% CI 1.32 to 1.66), stroke (HR 1.27, 95% CI 1.05 to 1.53), heart failure (HR 1.29, 95% CI 1.20 to 1.40) and bleeding (HR 1.26, 95% CI 1.09 to 1.47) at 1 year.ConclusionA concurrent PAD diagnosis was independently significantly associated with higher rates of adverse outcomes following MI in a nationwide real-life MI population. The low prevalence of PAD compared with previous studies suggests significant underdiagnosing. Future studies should investigate if PAD screening with ankle–brachial index may increase diagnosing and subsequently lead to improved treatment of polyvascular disease
Prognostic Value of Residual Disease after Neoadjuvant Therapy in HER2-Positive Breast Cancer Evaluated by Residual Cancer Burden, Neoadjuvant Response Index, and Neo-Bioscore
Authors: Steenbruggen Tessa G. , van Seijen Maartje , Janssen Liselore M. , van Ramshorst Mette S. , van Werkhoven Erik , Vrancken Peeters Marie-Jeanne T.D.F. , Wesseling Jelle , Lips Esther H. , Sonke Gabe S. 
Published: May 2019

Abstract

Purpose:
In breast cancer, pathologic complete response (pCR) to neoadjuvant systemic therapy (NST) is associated with favorable long-term outcome. Trastuzumab emtansine as additional adjuvant therapy improves recurrence-free survival of patients with HER2-positive breast cancer without pCR, but it is uncertain whether all patients without pCR need additional therapy. We evaluated the prognostic value of residual disease after trastuzumab-based NST in patients with HER2-positive breast cancer using Residual Cancer Burden (RCB), Neoadjuvant Response Index (NRI), and Neo-Bioscore.

Experimental Design:
We included patients with stage II or III HER2-positive breast cancer treated with trastuzumab-based NST and surgery at The Netherlands Cancer Institute between 2004 and 2016. RCB, NRI, and Neo-Bioscore were determined. Primary endpoint was 5-year recurrence-free interval (RFI). A 3% difference compared with the pCR group was considered acceptable as noninferiority margin on the 5-year RFI estimate, based on a proportional hazards model, and its lower 95% confidence boundary.

Results:
A total of 283 women were included. Median follow-up was 67 months (interquartile range 44–100). A total of 157 patients (56%) with pCR (breast and axilla) had a 5-year RFI of 92% (95% CI, 88–97); patients without pCR had a 5-year RFI of 80% (95% CI, 72–88). Patients with an RCB = 1 (N = 40, 15%), an NRI score between 0.75 and 0.99 (N = 30, 11%), or a Neo-Bioscore of 0 to 1 (without pCR; N = 28, 11%) have a 5-year RFI that falls within a predefined noninferiority margin of 3% compared with patients with pCR.

Conclusions:
The RCB, NRI, and Neo-Bioscore can identify patients with HER2-positive breast cancer with minimal residual disease (i.e., RCB = 1, NRI ≥ 0.75, or Neo-Bioscore = 0–1) after NST who have similar 5-year RFI compared with patients with pCR.
Overcoming the Blood–Brain Barrier with an Implantable Ultrasound Device
Authors: Sonabend Adam M. , Stupp Roger 
Published: May 2019

Abstract
Ultrasound-based blood–brain barrier disruption enhances drug delivery. To bypass the human skull, an implantable ultrasound emitter was developed, and proven safe and feasible in a first-in-human trial. Next development steps aim for larger field of disruption, quantification of drug levels, use of various drugs, and ultimately a pivotal trial demonstrating improved outcome.
See related article by Idbaih et al., p. 3793
Abstract SY02-01: Imaging the metastatic process
Authors: Sahai Erik 
Published: May 2019

Abstract
The acquisition of invasive behaviour enables the tumour cells to move into either the surrounding tissue or the vasculature and thereby spread to other parts of the body. The focus of our research is investigating why cancer cells become invasive and how they move. Until recently research into cancer cell movement has used highly artificial environments that do not accurately mimic the tumour environment leading to many contradictory results that could not be confirmed in vivo. The tumour environment is highly complex with numerous non-tumour cell types, variable blood flow and a diverse range of extracellular matrix components. To study cell motility in this environment we perform intravital multi-photon confocal imaging of tumours in anaesthetised mice. To complement intravital imaging, we have established a range of three-dimensional ‘organotypic’ cultures that allow us to model many aspects of the tumour environment in vitro. By using these systems it has become clear that there are a variety of different ways in which tumour cells can move. In particular, we are interested in the rapid movement of ‘amorphous’ single cells, termed amoeboid, and the slower collective movement of cohesive groups of cancer cells. The presentation will be split into two parts: the first part will focus on imaging the activity of signalling pathways that promote amoeboid motility while the second part will focus on the mechanism of collective cancer cell invasion.
Citation Format: Erik Sahai. Imaging the metastatic process [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY02-01
Abstract SY02-04: Regulation of invadopodia formation and cancer cell invasion
Authors: Blouw Barbara , Buschman Matt , Cejudo-Martin Pilar , Diaz Begoña , Gould Christine , Murphy Danielle , Quintavalle Manuela , Heynen Susanne , Azimi Behrad , Price Jeff , Courtneidge Sara A. 
Published: May 2019

Abstract
Cell invasion plays a central role in a wide variety of biological phenomena, and is the cause of tumor growth and metastasis. Understanding the biochemical mechanisms that control cell invasion is one of the major goals of our laboratory. Podosomes and invadopodia are specialized cellular structures present in cells with physiological or pathological invasive behaviors. These transient structures are localized at the ventral cell surface, contain an array of different proteins, and facilitate cell-substrate adhesion as well as the local proteolytic activity necessary for extracellular matrix remodeling and subsequent cellular invasion. We have previously shown that the adaptor protein and Src substrate Tks5 is required for both podosome and invadopodia formation, and for tumor growth in vivo. More recently we also defined a role for the Tks5-mediated generation of reactive oxygen species (ROS). We have developed a high content, cell-based high throughput screening assay that allows us to identify inhibitors and activators of invadopodia formation. As a proof of principle, we tested the LOPAC1280 collection of small molecules and found 7 inhibitory compounds and 2 activators. Of the 7 inhibitors, 4 are cyclin-dependent kinase (Cdk) inhibitors. Loss-of-function experiments demonstrated that Cdk5 is the responsible kinase. On the other hand, paclitaxel was one of the two compounds that increased invadopodia formation. We have also used our high content assay to screen a large compound collection as well as an siRNA library targeting the entire kinome. The mechanisms by which Cdk5 and tubulin regulate invadopodia formation, and the nature of the other regulators, are the subjects of our current investigations.
Citation Format: Barbara Blouw, Matt Buschman, Pilar Cejudo-Martin, Begoña Diaz, Christine Gould, Danielle Murphy, Manuela Quintavalle, Susanne Heynen, Behrad Azimi, Jeff Price, Sara A. Courtneidge. Regulation of invadopodia formation and cancer cell invasion [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY02-04
Abstract SY03-03: Modulating innate and adaptive immunity through the manipulation of dendritic cells
Authors: Bhardwaj Nina 
Published: May 2019

Abstract
Dendritic cells (DC) are potent antigen presenting cells used in clinical trials to treat cancer and infectious diseases such as HIV. We have performed two types of clinical trials to evaluate their immunogenicity in vivo. First, we compared DC to conventional vaccine adjuvants. HLA-A2+ resected melanoma patients were enrolled into a randomized clinical trial to compare vaccines comprised of six HLA-A2-restricted peptide antigens and a foreign protein, KLH, either pulsed onto cytokine-matured, monocyte-derived DCs or emulsified in the mineral oil adjuvant Montanide ISA 51. The frequency, magnitude and quality of antigen-specific cellular immune responses in peripheral blood were found to be greater in patients receiving the Montanide vaccine. Furthermore, the primed cells were functionally superior, indicating a need to improve current DC-based vaccine approaches. Preclinical studies in mice were undertaken to evaluate the mechanism by which DC prime T cells. Contrary to previous assumptions, we found that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells. This reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches will focus on creating DC vaccines that are more effective at directly priming T cells, by altering maturation factors, or abrogating the tumor induced suppression of endogenous DCs
In a second approach, we used TLR agonists targeting TLR 7, 8 and/or 9 to prime immunity to melanoma associated antigens in a series of clinical trials. They include imiquimod, resiquimod and CpG, agonists for TLR7 and/or TLR 8 and TLR9 respectively. These adjuvants when combined with the cancer testis antigen NY-ESO-1, induced integrated immune responses which were characterized by the induction of both CD4+ and CD8+ T cell immunity as well as antigen-specific antibodies in patients with resected melanoma. Strategies to optimize these various approaches to induce immunity in cancer and other chronic diseases will be discussed.
Citation Format: Nina Bhardwaj. Modulating innate and adaptive immunity through the manipulation of dendritic cells [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY03-03
Abstract SY15-01: Using comparative oncogenomics to guide personalized cancer medicine
Authors: DePinho Ronald A. 
Published: May 2019

Abstract
We exploited mouse models of cancer to identify prognosis determinants for guiding the management of early stage cancer such as prostate cancer. In the case of prostate cancer, effective management has beenchallenged by an elemental understanding of the genetic elements governingdisease progression. We hypothesized that pathways constraining invasive andmetastatic progression would be activated in indolent Pten null mouse prostatecancers and that deactivation of such progression checkpoints would occur upon disease progression in human prostate cancer. Using comparative transcriptomicand pathway analysis, we identifed and biochemically/genetically validated a TGFβ progression block which upon neutralization generates a lethal metastaticphentoype. This use of this metastatic mouse prostate cancer model, then enabled identification of a signature which, upon intersection with human data, can dichotomize men into high and low risk groups for progression.
Citation Format: Ronald A. DePinho. Using comparative oncogenomics to guide personalized cancer medicine [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY15-01
Abstract SY19-01: Cell to cell variability in the responses of tumor cells to death ligands
Authors: Sorger Peter K. , Spencer Sabrina , Flusberg Deborah , Gaudet Suzanne 
Published: May 2019

Abstract
Cell to cell variability in phenotype and fate is important for tissue homeostasis, the emergence of drug resistance and the evolution of tumors. I will discuss cell to cell variability in the responses of clonal populations of human cells to TRAIL, a prototypical inducer of receptor-mediated (extrinsic) apoptosis and an investigational therapeutic. Some TRAIL-treated human cells die within ~40 min, others only after 12 hr and some live indefinitely. During this variable delay initiator caspases (ICs) are active in processing substrates such as Bid and downstream effector caspases (ECs) but mitochondrial membrane permeablization (MOMP) does not occur and ECs are catalytically inactive. We have explored three explanations for cell to cell differences among members of a clonal and notionally uniform population: (i) genetic or epigenetic variation; (ii) the involvement of one or more biochemical processes subject to stochastic fluctuation; (iii) difference in cell state such as position in the cell cycle or protein concentrations.
To distinguish among these three possibilities we compared the fates of sister cells exposed to TRAIL using live-cell microscopy. Genetic and epigenetic factors are transmitted with near-perfect fidelity; reaction rates dominated by stochastic fluctuations are no more similar in sisters than in any two cells chosen at random and variability arising from differences in mRNA or protein levels should be transiently heritable (because division is a binomial process in which sister cells inherit roughly equal numbers of abundant cytosolic and nuclear factors but drift towards the population average over time). The later explanation is correct; natural fluctuations in protein levels dominate phenotypic heterogeneity in extrinsic apoptosis and cause transient phenotypic heritablility. Variability can be manipulated by protein over-expression and drugs and I will describe analytic methods for modeling these perturbations. Finally, I will show that natural variation is sufficient to cause some cells to follow one biochemical pathway to death (a MOMP-dependent Type II pathway) and another set of genetically identical cells to follow a fundamentally different pathway (a MOMP-independent Type I pathway).
Citation Format: Peter K. Sorger, Sabrina Spencer, Deborah Flusberg, Suzanne Gaudet. Cell to cell variability in the responses of tumor cells to death ligands [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY19-01
Abstract SY27-01: Differential efficacy of the angiogenesis inhibitor thrombospondin-1 in different organs
Authors: Baek Kwan-Hyuck , Lee Yoon Jin , Karl Daniel , Zaslavsky Alexander , Yoon Sam , Ryeom Sandra W. 
Published: May 2019

Abstract
Tumor angiogenesis is negatively regulated by a number of angiogenesis inhibitors, of which thrombospondin-1 (TSP-1) is one of the most potent. We examined the efficacy of TSP-1 in suppressing tumor growth using both transplantable and inducible tumor and metastasis models in the lung and liver. Although the lung exhibits high levels of endogenous TSP-1, experimental metastases in the lungs of Tsp-1-/- mice showed no differences in growth or microvessel density compared to wild-type mice. However, experimental metastases in the liver were significantly increased in Tsp-1-/- mice versus wild-type mice. Similarly, the growth of tumor cells over-expressing TSP-1 was dramatically inhibited when inoculated into the liver but not in the lung. To further investigate the function of TSP-1 in the lung, we utilized an inducible lung tumor model driven by sporadic activation of oncogenic K-ras. The progression of benign lesions is restrained, in part, by oncogenic activation of cellular senescence. Oncogenic Ras is a prototypical example of this, triggering senescence in many cell types, including lung epithelium. The loss of TSP-1 in this inducible genetically engineered mouse model of lung cancer led to a significant increase in tumor progression. Unexpectedly, we found that TSP-1 plays a critical but previously unidentified role in suppressing K-ras-induced lung tumorigenesis by mediating senescence. Oncogenic ras-induced senescence is abrogated by Tsp-1 deficiency, leading to a marked decrease in overall survival of mice. Similarly, Tsp-1-/- fibroblasts are refractory to oncogenic Ras-induced senescence, which is restored upon TSP-1 re-expression. Moreover, K-ras induces TSP-1 upregulation in a p53-dependent manner. Together, these data indicate that TSP-1 is a critical and cell-autonomous mediator of oncogenic Ras-induced senescence in the lung and suggests a novel role for TSP-1 in the lung, independent of its anti-angiogenic function.
Citation Format: Kwan-Hyuck Baek, Yoon Jin Lee, Daniel Karl, Alexander Zaslavsky, Sam Yoon, Sandra W. Ryeom. Differential efficacy of the angiogenesis inhibitor thrombospondin-1 in different organs [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY27-01