bluuebunny/crossref_metadata_2025_split huggingface dataset:
STEM-09. INTRINSIC TUMOR PLASTICITY IN GLIOBLASTOMA ALLOWS FOR RECREATION OF STEM LIKE-STATES AND EFFICIENT TUMOR CELL ADAPTATION TO NEW MICROENVIRONMENTS
Authors: Golebiewska Anna , Dirkse Anne , Buder Thomas , Yabo Yahaya A , Muller Arnaud , Nazarov Petr V , Bjerkvig Rolf , Skupin Alexander , Poovathingal Suresh K , Herold-Mende Christel , Voss Anja , Deutsch Andreas , Niclou Simone 
Published: November 2019

Abstract

BACKGROUND
Cellular heterogeneity is a hallmark of numerous cancer types, including Glioblastoma (GBM). Cancer stem cells (CSC) have been accounted for the generation of phenotypic heterogeneity and tumor progression in GBM. Recent data, however, suggest that CSCs may not represent a stable entity and intrinsic plasticity plays a key role in tumor adaptation to changing microenvironments. The question arises whether CSCs are a defined subpopulation of GBM or whether they represent a cellular state that any cancer cell can adopt.

METHODS
We interrogated intra-tumoral phenotypic heterogeneity at the single cell transcriptomic and proteomic level in GBM biopsies, patient-derived stem-like cultures and orthotopic xenografts (PDOXs). Tumor cell subpopulations, classified based on their expression of four proposed stem cell markers (CD133, CD15, A2B5 and CD44), were FACS isolated and functionally characterized under various microenvironmental conditions. Mathematical Markov modelling was applied to calculate state transitions.

RESULTS
GBM patient biopsies, PDOXs and stem-like cell cultures displayed remarkable stem cell-associated intra-tumoral heterogeneity. However independent of marker expression, all analysed tumor subpopulations carried stem-cell properties and recreated phenotypic heterogeneity. Mathematical modeling revealed a different propensity in reforming heterogeneity over time, which was independent of the proliferation index but linked to in vivo tumorigenic potential. Although GBM subpopulations varied in their potential to adapt to new environments, all were able to reach a steady state microenvironment-specific equilibrium.

CONCLUSIONS
Our results suggest that phenotypic heterogeneity in GBM results from intrinsic plasticity allowing tumor cells to adapt to changing microenvironmental conditions. Cellular states are non-hierarchical, reversible and occur via stochastic state transitions, striving towards a microenvironment-instructed equilibrium. Our data provides evidence that CSCs do not represent a defined clonal entity, but rather a cellular state determined by environmental conditions, which has implications for the design of treatment strategies targeting CSC-like states.
STEM-23. METASTATIC BRAIN TUMOR IMAGING THROUGH TARGETED PEPTIDES ISOLATED VIA PHAGE DISPLAY BIOPANNING AGAINST BRAIN METASTASIS-INITIATING CELLS
Authors: Kim JongMyung , Liu James 
Published: November 2019

Abstract
To effectively target metastatic brain tumors (MBTs), the paradigm of initiating treatment against MBTs following detection on clinical imaging needs to be shifted to an understanding of the mechanisms that drive the formation and maintenance of brain metastasis-initiating cells (BMICs). Targeting this tumor sub-population, which may form as a result of activation of the epithelial-mesenchymal transition, may allow for more effective means of understanding and targeting brain metastases. In order to isolate BMICs, we have harvested cells from patient derived MBTs originating from lung cancer and cultured the cells using stem cell media conditions. We then performed in vitro and in vivo phage display biopanning to isolate 12-amino acid length peptides that specifically target BMICs. Several peptides were isolated from both in vitro and in vivo biopanning strategies. Of the peptides recovered, one peptide, LBM4, demonstrated specific binding to MBT cells over primary lung cancer cells in vitro through flow cytometry analysis and immunocytochemistry. Fluorescent tagged LBM4 intravenously injected into mice harboring intracranial brain metastases demonstrated peptide localization to the tumor within the intracranial cavity visualized with live animal imaging. Peptide imaging of tumor corresponded to MRI imaging confirming that the peptides could serve as an alternative to tumor imaging, with the potential for greater sensitivity resulting from the cellular targeting of MBTs. Our results demonstrate that we can use a combination of in vitro and in vivo phage display biopanning to isolate cell specific targeting peptides. MBT targeting peptides can potentially result in a shifting of the clinical treatment paradigm of brain metastases, through the development of more effective targeted therapeutics aimed at BMICs, as well as improving detection of MBT cells which may result in earlier tumor visualization, as well as delineation of tumor recurrence versus radiation effects.
A phase III double-blind placebo-controlled randomized study of dexamphetamine sulfate for fatigue in primary brain tumors patients: An ANOCEF trial (DXA)
Authors: Laigle-Donadey Florence , Ducray François , Boone Matthieu , Diallo Mamadou Hassimiou , Hajage David , Ramirez Carole , Chinot Olivier , Ricard Damien , Delattre Jean-Yves 
Published: November 2019

Abstract

Background
Most patients suffering from a primary brain tumor (PBT) complain of chronic fatigue affecting their quality of life (QOL). We hypothesized that dexamphetamine sulfate, a psychostimulant drug, could improve fatigue in PBT patients.

Methods
A double-blind, phase III, multi-institutional, placebo-controlled randomized trial (1:1 allocation) assessed the efficacy and tolerability of dexamphetamine at a dosage of 30 mg/day in PBT patients with stable disease who complained of severe fatigue, defined as a Multidimensional Fatigue Inventory (MFI-20) score ≥60. The primary outcome was the variation of the MFI 20 score between inclusion and the evaluation at 3 months in nonprogressive patients. Mood, QOL and cognitive function were also evaluated.

Results
From April 2013 to November 2016, 46 patients were enrolled in the study, 41 of whom were evaluable for analysis (dexamphetamine group: 22; placebo group: 19). Tolerance was generally good, with no treatment-related deaths and no grade 4 toxicity. Patients in the dexamphetamine arm complained more frequently of psychiatric side effects (mostly hyperactivity, anxiety, sleep disorder, and irritability) than patients in the placebo arm (P = .018). There were no statistically significant differences at 3 months between the dexamphetamine and placebo arms in any of the outcomes (MFI-20, Norris Visual Analog Scale, Hospital Anxiety and Depression Scale (HADS), QOL (EORTC QLQ-C30/BN 20), Marin’s Apathy Evaluation Scale, and cognitive evaluations).

Conclusion
Dexamphetamine at a dosage of up to 30 mg/day for 3 months has acceptable tolerability in PBT patients but does not improve fatigue, cognitive function, or QOL.
How Do Physical Therapists Approach Management of People With Early Knee Osteoarthritis? A Qualitative Study
Authors: MacKay Crystal , Hawker Gillian A , Jaglal Susan B 
Published: November 2019

Abstract

Background
Knee osteoarthritis (OA) is a leading cause of disability. There is increasing emphasis on initiating treatment earlier in the disease. Physical therapists are central to the management of OA through the delivery of exercise programs. There is a paucity of research on physical therapists’ perceptions and clinical behaviors related to early knee OA management.

Objective
The study aimed to explore how physical therapists approached management of early knee OA, with a focus on evidence-based strategies. This is an important first step to begin to optimize care by physical therapists for this population.

Design
We used a qualitative, descriptive research design.

Methods
Semistructured interviews were conducted with 33 physical therapists working with people with knee symptoms and/or diagnosed knee OA in community or outpatient settings in Canada. Data were analyzed using thematic analysis.

Results
Five main themes were constructed: (1) Physical therapists’ experience and training: clinical experiences and continuing professional development informed clinical decision-making. (2) Tailoring treatment from the physical therapist “toolbox:” participants described their toolbox of therapeutic interventions, highlighting the importance of tailoring treatments to people. (3) The central role of exercise and physical activity in management: exercise was consistently recommended by participants. (4) Variability in support for weight management: there was variation related to how participants addressed weight management. (5) Facilitating “buy-in” to management: physical therapists used a range of strategies to gain “buy-in.”

Limitations
Participants were recruited through a professional association specializing in orthopedic physical therapy and worked an average of 21 years.

Conclusions
Participants’ accounts emphasized tailoring of interventions, particularly exercises, which is an evidence-based strategy for OA. Findings illuminated variations in management that warrant further exploration to optimize early intervention (eg, weight management, behavior change techniques).
Cervical Sensorimotor Control Does Not Change Over Time and Is Not Related to Chronic Idiopathic Neck Pain Characteristics: A 6-Month Longitudinal Observational Study
Authors: de Zoete Rutger M J , Osmotherly Peter G , Rivett Darren A , Snodgrass Suzanne J 
Published: November 2019

Abstract

Background
Cervical sensorimotor control (CSMC) outcomes have been suggested to be important in the assessment of individuals with neck pain, despite the lack of consistent supporting evidence that CSMC skills are related to neck pain.

Objective
The aim of this study was to investigate whether CSMC changes over time in individuals with chronic idiopathic neck pain and whether neck pain characteristics are associated with CSMC.

Design
A longitudinal observational study was performed.

Methods
A total 50 participants with chronic idiopathic neck pain and 50 matched participants who were healthy (controls) completed 7 CSMC tests (including 14 test conditions): joint position error, postural balance, subjective visual vertical, head tilt response, The Fly, smooth pursuit neck torsion, and head steadiness. Neck pain characteristics included pain intensity (visual analog scale), pain duration, and neck disability (Neck Disability Index). Linear mixed models were used to investigate whether any factors were associated with changes in CSMC.

Results
Neck pain intensity was associated with 1 of 14 CSMC test conditions (balance with torsion and eyes open), and neck disability was associated with balance with eyes open and high-load head steadiness. Other factors, including sex, age, body mass index, physical activity levels, and neck pain duration, showed no association with CSMC.

Limitations
Although all other tests involved computerized data collection, the joint position error test was administered manually, introducing the risk of researcher bias.

Conclusions
The few associations between test conditions and neck pain characteristics were at best weak; hence, these are likely to be chance findings. These results suggest that CSMC may not be associated with improvement/worsening of chronic idiopathic neck pain, spawning debate on the clinical usefulness of CSMC tests.
A Cayman Islands update on wills and trusts
Authors: Davern Raymond , Way Alex 
Published: November 2019

Abstract
This article looks at the principal provisions of two pieces of recent Cayman Islands legislation that are now in force and that are likely to be of interest generally to international private client practitioners: the Formal Validity of Wills (Persons Dying Abroad) Law, 2018 and the Trusts (Amendment) Law, 2019.
Spatial patterns of leptospirosis in Ecuador, 2013–2018
Authors: Núñez-González Solange , Gault Christopher , Granja Patricia , Simancas-Racines Daniel 
Published: November 2019

Abstract

Background
Leptospirosis is a zoonotic disease that is considered an important public health problem in tropical regions and the world's poorest countries.

Methods
In this ecological study, we included cases of leptospirosis reported in Ecuador from 2013 to 2018. Spatial autocorrelation was evaluated through the global Moran I index and spatial-temporal scan statistics were used to identify high-risk clusters.

Results
In Ecuador, the leptospirosis incidence rates decreased from 3.3 cases per 100 000 population in 2013 to 0.8 cases per 100 000 population in 2018. The global Moran I index for the study period showed a positive spatial autocorrelation (0.68; p=0.001). We identified three significant spatial-temporal clusters for a high occurrence of leptospirosis incidence located in cantons of the Coast and Amazon regions.

Conclusions
The clusters identified could be targeted by policymakers and stakeholders in order to direct surveillance and understand the dynamics of the distribution of leptospirosis in Ecuador.
Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease
Authors: Robak Laurie A. , Du Renqian , Yuan Bo , Gu Shen , Alfradique-Dunham Isabel , Kondapalli Vismaya , Hinojosa Evelyn , Stillwell Amanda , Young Emily , Zhang Chaofan , Song Xiaofei , Du Haowei , Gambin Tomasz , Jhangiani Shalini N. , Akdemir Zeynep Coban , Muzny Donna M. , Tejomurtula Anusha , Ross Owen A. , Shaw Chad , Jankovic Joseph , Bi Weimin , Posey Jennifer E. , Lupski James R. , Shulman Joshua M. 
Published: November 2019

AbstractBackgroundParkinson’s disease (PD) is a genetically heterogeneous condition; both single nucleotide variants (SNVs) and copy number variants (CNVs) are important genetic risk factors. We examined the utility of combining exome sequencing and genome-wide array-based comparative genomic hybridization (aCGH) for identification of PD genetic risk factors.MethodsWe performed exome sequencing on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated exome sequencing and array comparative genomic hybridization data for pathogenic SNVs and CNVs at Mendelian PD gene loci. SNVs were confirmed via Sanger sequencing. CNVs were confirmed with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing.ResultsUsing exome sequencing, we discovered individuals with known pathogenic single nucleotide variants in GBA (p.E365K, p.T408M, p.N409S, p.L483P) and LRRK2 (p.R1441G and p.G2019S). Two subjects were each double heterozygotes for variants in GBA and LRRK2. Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.N52fs, p.T240M, p.P437L, p.W453*) and likely disrupting CNVs at the PARK2 locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors.ConclusionsIntegrated exome sequencing and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PARK2 CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.
Broadly neutralizing plasma antibodies effective against diverse autologous circulating viruses in infants with multivariant HIV-1 infection
Authors: Mishra Nitesh , Sharma Shaifali , Dobhal Ayushman , Kumar Sanjeev , Chawla Himanshi , Singh Ravinder , Makhdoomi Muzamil Ashraf , Das Bimal Kumar , Lodha Rakesh , Kabra Sushil Kumar , Luthra Kalpana 
Published: November 2019

AbstractDue to the extensive antigenic diversity of human immunodeficiency virus-1 (HIV-1), broadly neutralizing antibodies (bnAbs) develop in a subset of infected individuals over 2-3 years of infection. Interestingly, infected infants have been shown to develop plasma bnAbs frequently and as early as one-year post-infection, with features atypical than adult bnAbs, suggesting that the factors governing bnAb induction in infants are distinct from that in adults. Understanding the viral characteristics in infected infants with early bnAb responses will provide key information on the antigenic triggers driving B cell maturation pathways towards the induction of bnAbs. Herein, we evaluated the presence of plasma bnAbs in a cohort of 51 HIV-1 clade C perinatally infected infants of Indian origin and identified viral factors associated with early bnAb responses. Plasma bnAbs targeting V2-apex on the env were predominant in infant elite and broad neutralizers. Circulating viral variants in infant elite neutralizers were susceptible to known bnAbs against V2-apex while varied resistance profile to other bnAb classes was observed. In infant elite neutralizers, multivariant infection was associated with plasma bnAbs targeting diverse autologous viruses. Our data provides information supportive of polyvalent vaccination approaches capable of inducing V2-apex bnAbs against HIV-1.
Light-Sheet Fluorescence Microscopy with Scanning Non-diffracting Beams
Authors: Kafian Hosein , Lalenejad Meelad , Moradi-Mehr Sahar , Akbari Birgani Shiva , Abdollahpour Daryoush 
Published: November 2019

AbstractLight-sheet fluorescence microscopy (LSFM) has now become a unique technique in different fields ranging from three-dimensional (3D) tissue imaging to real-time functional imaging of neuronal activities. Nevertheless, obtaining high-quality artifact-free images from large, dense and inhomogeneous samples is the main challenge of the method that still needs to be adequately addressed. Here, we demonstrate significant enhancement of LSFM image qualities by using scanning non-diffracting illuminating beams, both through experimental and numerical investigations. The effect of static and scanning illumination with several beams are analyzed and compared, and it is shown that scanning 2D Airy light sheet is minimally affected by the artifacts, and provide higher contrasts and uniform resolution over a wide field-of-view, due to its reduced spatial coherence, self-healing feature and higher penetration depth. Further, the capabilities of the illumination scheme is utilized for both single and double wavelength 3D imaging of a large and dense mammospheres of cancer tumor cells as complex inhomogeneous biological samples.
The Hippo pathway origin and its oncogenic alteration in evolution
Authors: Chen Yuxuan , Han Han , Seo Gayoung , Vargas Rebecca , Yang Bing , Chuc Kimberly , Zhao Huabin , Wang Wenqi 
Published: November 2019

AbstractThe Hippo pathway is a central regulator of organ size and a key tumor suppressor via coordinating cell proliferation and death. Initially discovered in Drosophila, the Hippo pathway has been implicated as an evolutionarily conserved pathway in mammals; however, how this pathway was evolved to be functional from its origin is still largely unknown. In this study, we traced the Hippo pathway in premetazoan species, characterized the intrinsic functions of its ancestor components, and unveiled the evolutionary history of this key signaling pathway from its unicellular origin. In addition, we elucidated the paralogous gene history for the mammalian Hippo pathway components and characterized their cancer-derived somatic mutations from an evolutionary perspective. Taken together, our findings not only traced the conserved function of the Hippo pathway to its unicellular ancestor components, but also provided novel evolutionary insights into the Hippo pathway organization and oncogenic alteration.
Supplemented nutrition increases immunity and drug efficacy in a natural host-helminth system
Authors: Sweeny Amy R. , Clerc Melanie , Pontifes Paulina A. , Venkatesan Saudamini , Babayan Simon A. , Pedersen Amy B. 
Published: November 2019

AbstractGastrointestinal helminths are common parasites of humans, wildlife, and livestock, leading to chronic infections in large parts of the world. In humans, there is also an overlap in the incidence of malnutrition and helminth infections which can predispose individuals to higher infection burdens and reduced anthelmintic efficacy due to compromised immunity. This relationship has been well-studied in laboratory models by testing for the impact of dramatic reductions of specific nutrients on infection outcomes. However, much less is known about the benefits of whole-diet supplementation in natural host-helminth systems. We experimentally supplemented the diet of wood mice (Apodemus sylvaticus) and measured resistance to the gastrointestinal nematode Heligmosomoides polygyrus and anthelmintic treatment efficacy in both natural and captive populations. Supplemented wood mice were more resistant to H. polygyrus infection, cleared worms more efficiently after treatment, produced stronger general and parasite-specific antibody responses, and maintained better body condition. In addition, supplemented nutrition in conjunction with anthelminthic treatment significantly reduced H. polygyrus transmission potential. These large-scale improvements in condition and immunity of supplemented nutrition found in controlled and wild environments show the rapid and extensive benefits of a well-balanced diet and have important implications for using diet interventions to improve disease control programmes.Author SummaryGastrointestinal helminths are ubiquitous parasites which cause chronic infections and debilitating symptoms worldwide for human and animal populations alike. Efforts to control helminth infections rely primarily on deworming drugs. However, despite high availability and low cost of these drugs, reinfection is common and helminths remain a substantial problem in many areas of the world. One factor which contributes to the persistence of helminth infections is co-occurrence of malnutrition. Extensive work in model laboratory systems has shown that deficiencies in both macro- and micronutrients can impair host immune responses to helminth infections, but how this relationship translates to natural host-helminth systems and drug efficacy is still poorly understood. Here, we used a combination of experimental nutrition supplementation and deworming treatment in paired wood mouse populations in both wild and captive environments to determine the role of a well-balanced diet for infection control in a natural host-helminth system. We found that mice on a supplemented diet had lower burden of infection and increased drug efficacy, body condition, and immune responses. We also found that supplementation lowered transmission potential of hosts. These broad and rapid effects of increased nutrition quality have important implications for the benefits of diet interventions alongside deworming drugs.