bluuebunny/crossref_metadata_2025_split huggingface dataset:
The tumor immune microenvironment of primary and metastatic HER2− positive breast cancers utilizing gene expression and spatial proteomic profiling
Authors: Schlam Ilana , Church Sarah E. , Hether Tyler D. , Chaldekas Krysta , Hudson Briana M. , White Andrew M. , Maisonet Emily , Harris Brent T. , Swain Sandra M. 
Published: November 2021

AbstractBackgroundThe characterization of the immune component of the tumor microenvironment (TME) of human epidermal growth factor receptor 2 positive (HER2+) breast cancer has been limited. Molecular and spatial characterization of HER2+ TME of primary, recurrent, and metastatic breast tumors has the potential to identify immune mediated mechanisms and biomarker targets that could be used to guide selection of therapies.MethodsWe examined 15 specimens from eight patients with HER2+ breast cancer: 10 primary breast tumors (PBT), two soft tissue, one lung, and two brain metastases (BM). Using molecular profiling by bulk gene expression TME signatures, including the Tumor Inflammation Signature (TIS) and PAM50 subtyping, as well as spatial characterization of immune hot, warm, and cold regions in the stroma and tumor epithelium using 64 protein targets on the GeoMx Digital Spatial Profiler.ResultsPBT had higher infiltration of immune cells relative to metastatic sites and higher protein and gene expression of immune activation markers when compared to metastatic sites. TIS scores were lower in metastases, particularly in BM. BM also had less immune infiltration overall, but in the stromal compartment with the highest density of immune infiltration had similar levels of T cells that were less activated than PBT stromal regions suggesting immune exclusion in the tumor epithelium.ConclusionsOur findings show stromal and tumor localized immune cells in the TME are more active in primary versus metastatic disease. This suggests patients with early HER2+ breast cancer could have more benefit from immune-targeting therapies than patients with advanced disease.
CRISPR/Cas9-mediated TGFβRII disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells in vitro
Authors: Alishah Khadijeh , Birtel Matthias , Masoumi Elham , Jafarzadeh Leila , Mirzaee Hamid Reza , Hadjati Jamshid , Voss Ralf-Holger , Diken Mustafa , Asad Sedighe 
Published: November 2021

Abstract
Background
CAR T-cell therapy has been recently unveiled as one of the most promising cancer therapies in hematological malignancies. However, solid tumors mount a profound line of defense to escape immunosurveillance by CAR T-cells. Among them, cytokines with an inhibitory impact on the immune system such as IL-10 and TGFβ are of great importance: TGFβ is a pleiotropic cytokine, which potently suppresses the immune system and is secreted by a couple of TME resident and tumor cells.

Methods
In this study, we hypothesized that knocking out the TGFβ receptor II gene, could improve CAR T-cell functions in vitro and in vivo. Hereby, we used the CRISPR/Cas9 system, to knockout the TGFβRII gene in T-cells and could monitor the efficient gene knock out by genome analysis techniques. Next, Mesothelin or Claudin 6 specific CAR constructs were overexpressed via IVT-RNA electroporation or retroviral transduction and the poly-functionality of these TGFβRII KO CAR T-cells in terms of proliferation, cytokine secretion and cytotoxicity were assessed and compared with parental CAR T-cells.

Results
Our experiments demonstrated that TGFβRII KO CAR T-cells fully retained their capabilities in killing tumor antigen positive target cells and more intriguingly, could resist the anti-proliferative effect of exogenous TGFβ in vitro outperforming wild type CAR T-cells. Noteworthy, no antigen or growth factor-independent proliferation of these TGFβRII KO CAR T-cells has been recorded. TGFβRII KO CAR T-cells also resisted the suppressive effect of induced regulatory T-cells in vitro to a larger extent. Repetitive antigen stimulation demonstrated that these TGFβRII KO CAR T-cells will experience less activation induced exhaustion in comparison to the WT counterpart.

Conclusion
The TGFβRII KO approach may become an indispensable tool in immunotherapy of solid tumors, as it may surmount one of the key negative regulatory signaling pathways in T-cells.
Phospholipase A2 group IIA correlates with circulating high-density lipoprotein cholesterol and modulates cholesterol efflux possibly through regulation of PPAR-γ/LXR-α/ABCA1 in macrophages
Authors: Liang Ling , Xie Qiang , Sun Changqing , Wu Yuanhui , Zhang Wei , Li Weihua 
Published: November 2021

Abstract
Background
Secretory phospholipase A2 group IIA (sPLA2-IIA) is an independent risk factor for cardiovascular disease, but its role on high-density lipoprotein cholesterol (HDL-C) level has not been clarified. The aim of the present study was to explore the association between circulating sPLA2-IIA and HDL-C, and to evaluate if sPLA2-IIA enhances cholesterol efflux capacity through regulation of peroxisome proliferator-activated receptor γ (PPAR-γ), liver X receptor α (LXR-α), and ATP-binding cassette A1 (ABCA1).

Methods
131 patients with coronary artery disease were enrolled. The plasma level of sPLA2-IIA was tested with enzyme-linked immunosorbent assay kit, and serum lipids were assessed by biochemical analyzer. Human monocyte-macrophage cell line THP-1 was co-incubated with sPLA2-IIA in the presence/absence of selective PPAR-γ antagonist GW9662 in vitro. Real-time PCR and Western-blot were employed to measure the mRNA and protein expressions of PPAR-γ, LXR-α, and ABCA1, respectively. The cholesterol efflux was evaluated by using an assay kit.

Results
In subjects, circulating level of sPLA2-IIA was positively related with that of HDL-C (r = 0.196, p = 0.024). The plasma level of sPLA2-IIA was significantly higher in the high HDL-C (≥ 1.04 mmol/L) group (7477.828 pg/mL) than that in low HDL-C (< 1.04 mmol/L) group (5836.92 pg/mL, p = 0.004). For each increase of 1 pg/μl in sPLA2-IIA level, the adjusted odds ratio for HDL-C ≥ 1.04 mmol/L was 1.143. Co-incubation of THP-1 cells with sPLA2-IIA resulted in increased expressions of PPAR-γ, LXR-α, and ABCA1, as well as enhanced cholesterol efflux capacity, that were all reversed by administration of GW9662.

Conclusions
Circulating sPLA2-IIA was positively associated with HDL-C. PPAR-γ/LXR-α/ABCA1 might be responsible for sPLA2-IIA-regulated cholesterol efflux in macrophages.
Brain injury, endothelial injury and inflammatory markers are elevated and express sex-specific alterations after COVID-19
Authors: Savarraj Jude , Park Eun S. , Colpo Gabriela D. , Hinds Sarah N. , Morales Diego , Ahnstedt Hilda , Paz Atzhiry S. , Assing Andres , Liu Fudong , Juneja Shivanki , Kim Eunhee , Cho Sung-min , Gusdon Aaron M. , Dash Pramod , McCullough Louise D. , Choi H. Alex 
Published: November 2021

AbstractObjectiveAlthough COVID-19 is a respiratory disease, all organs can be affected including the brain. To date, specific investigations of brain injury markers (BIM) and endothelial injury markers (EIM) have been limited. Additionally, a male bias in disease severity and mortality after COVID-19 is evident globally. Sex differences in the immune response to COVID-19 may mediate this disparity. We investigated BIM, EIM and inflammatory cytokine/chemokine (CC) levels after COVID-19 and in across sexes.MethodsPlasma samples from 57 subjects at < 48 h of COVID-19 hospitalization, and 20 matched controls were interrogated for the levels of six BIMs—including GFAP, S100B, Syndecan-1, UCHLI, MAP2 and NSE, two EIMs—including sICAM1 and sVCAM1. Additionally, several cytokines/chemokines were analyzed by multiplex. Statistical and bioinformatics methods were used to measure differences in the marker profiles across (a) COVID-19 vs. controls and (b) men vs. women.ResultsThree BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNFα were significantly (p < 0.05) elevated in the COVID-19 cohort compared to controls. Bioinformatics analysis reveal a stronger positive association between BIM/CC/EIMs in the COVID-19 cohort. Analysis across sex revealed that several BIMs and CCs including NSE, IL10, IL15 and IL8 were significantly (p < 0.05) higher in men compared to women. Men also expressed a more robust BIM/ EIM/CC association profile compared to women.ConclusionThe acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.
Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation
Authors: Chu Erskine , Mychasiuk Richelle , Hibbs Margaret L. , Semple Bridgette D. 
Published: November 2021

AbstractMicroglia are integral mediators of innate immunity within the mammalian central nervous system. Typical microglial responses are transient, intending to restore homeostasis by orchestrating the removal of pathogens and debris and the regeneration of damaged neurons. However, prolonged and persistent microglial activation can drive chronic neuroinflammation and is associated with neurodegenerative disease. Recent evidence has revealed that abnormalities in microglial signaling pathways involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) may contribute to altered microglial activity and exacerbated neuroimmune responses. In this scoping review, the known and suspected roles of PI3K-AKT signaling in microglia, both during health and pathological states, will be examined, and the key microglial receptors that induce PI3K-AKT signaling in microglia will be described. Since aberrant signaling is correlated with neurodegenerative disease onset, the relationship between maladapted PI3K-AKT signaling and the development of neurodegenerative disease will also be explored. Finally, studies in which microglial PI3K-AKT signaling has been modulated will be highlighted, as this may prove to be a promising therapeutic approach for the future treatment of a range of neuroinflammatory conditions.
Period poverty: menstrual health hygiene issues among adolescent and young Venezuelan migrant women at the northwestern border of Brazil
Authors: Soeiro Rachel E. , Rocha Leila , Surita Fernanda G. , Bahamondes Luis , Costa Maria L. 
Published: November 2021

Abstract
Background
Adolescent and young women (10–24 years old) are habitually a neglected group in humanitarian settings. Menstrual hygiene management (MHM) is an unmet aspect of sexual and reproductive health (SRH) and an additional challenge if lack of hygiene products, inadequate access to safe, clean, and private toilets identified as period poverty. Our objective was to provide an overview of the main MHM issues affecting Venezuelan migrant adolescents and young women in the north-western border of Venezuela-Brazil.

Method
A cross-sectional study was conducted, early in 2021, with the use of a self-responded questionnaire, in Spanish, adapted from the Menstrual Practice Needs Scale (MPNS-36). All identified adolescents and young women aged between 12 and 24 years old were invited to participate (convenience sample-167 women). Women with complete questionnaires and who menstruate were included. Information on access to and quality of hygiene kits and toilets were retrieved, and a descriptive analysis performed, with an evaluation of frequencies for categorical variables (n, %) and mean (± SD-standard deviation) for continuous variables. In addition to the open-ended questions, we included one open question about their personal experience with menstruation.

Results
According to official reports, at the moment of the interviews, there were 1.603 Venezuelans living on the streets in Boa Vista. A total of 167 young women were invited, and 142 further included, mean age was 17.7 years, almost half of the participants who menstruate (46.4%) did not receive any hygiene kits, 61% were not able to wash their hands whenever they wanted, and the majority (75.9%) did not feel safe to use the toilets. Further, menstruation was often described with negative words.

Conclusions
Migrant Venezuelan adolescents and young women have their MHM needs overlooked, with evident period poverty, and require urgent attention. It is necessary to assure appropriate menstrual materials, education, and sanitation facilities, working in partnership among governmental and non-governmental organizations to guarantee menstrual dignity to these young women.
Association between experience of specific side-effects and contraceptive switching and discontinuation in Uganda: results from a longitudinal study
Authors: Zimmerman Linnea A. , Sarnak Dana O. , Karp Celia , Wood Shannon N. , Ahmed Saifuddin , Makumbi Fredrick , Kibira Simon P. S. 
Published: November 2021

Abstract
Background
There is substantial evidence that contraceptive side-effects are a major deterrent to consistent use of contraception but few studies in low- or middle-income countries explore the role of specific side-effects on contraceptive use dynamics. This study used population-based, longitudinal data to explore the effect of specific side-effects on contraceptive continuation, discontinuation, and switching in Uganda.

Methods
Data for this study come from two rounds of survey data collection in Uganda: PMA2020’s sixth cross-sectional survey and a follow-up survey conducted 1 year later. The main outcomes of interest were discontinuation and switching among users of hormonal contraceptive methods (implants, injectables and oral pill) and the IUD at baseline (n = 560). Multivariable logistic regressions assessed the association of experiencing specific side-effects (more bleeding, less bleeding, irregular bleeding, increased dryness/reduced libido, and physical discomfort) with discontinuation and switching 1 year later, adjusting for socio-demographic characteristics, type of method, and length of use. We also examined the differential effects of side-effects between discontinuation and switching risks.

Results
About 23% of hormonal and IUD contraceptive users reported experiencing side-effects at baseline survey. Overall, discontinuation and switching were higher among injectables and pill users, compared to IUD and implants users. Reporting more bleeding or less bleeding increased the odds of discontinuation and switching by 2.74 (95% CI 1.00–7.51) and 1.86 (1.04–3.34), respectively. There was no significant difference in discontinuation and switching by side-effects.

Conclusions
Greater attention should be paid to understanding the unique contributions of side-effects to contraceptive behavior using population-based data. While about a quarter of women reported experiencing side effects, those who experienced bleeding specific side effects were at higher risk of contraceptive discontinuation and switching. Providing greater individualized care that includes information and counseling about common side-effects, how they may impact daily life, and how tolerable these effects may be is necessary.
Determinants of women’s preferred and actual abortion provision locations in Nigeria
Authors: Byrne Meagan E. , Omoluabi Elizabeth , OlaOlorun Funmilola M. , Moreau Caroline , Bell Suzanne O. 
Published: November 2021

Abstract
Background
Unsafe abortion remains a leading cause of maternal mortality globally. Many factors can influence women’s decisions around where to seek abortion care; however, little research has been done on abortion care decisions at a population-level in low-resource settings, particularly where abortion is legally restricted.

Methods
This analysis uses data from a 2019–2020 follow-up survey of 1144 women in six Nigerian states who reported an abortion experience in a 2018 cross-sectional survey. We describe women’s preferred and actual primary abortion care provider/location by distinguishing clinical, pharmacy/chemist, or other non-clinical providers or locations. We also examine factors that influence women’s decisions about where to terminate their pregnancy and identify factors hindering women’s ability to operationalize their preferences. We then examine the characteristics of women who were not able to use their preferred provider/location.

Results
Non-clinical providers (55.0%) were more often used than clinical providers (45.0%); however, clinical providers were preferred by most women (55.6%). The largest discrepancies in actual versus preferred abortion provider/location were private hospitals (7.6% actual versus 37.2% preferred), government hospitals (4.3% versus 22.6%), chemists (26.5% versus 5.9%) and pharmacies (14.9% versus 6.6%). “Privacy/confidentiality” was the most common main reason driving women’s abortion provider/location choice (20.7%), followed by “convenience” (16.9%) and “recommended” by someone (12.3%), most often a friend (60.8%), although top reasons differed by type of provider/location. Cost and distance were the two most common reasons that women did not use their preferred provider/location (46.1% and 21.9%, respectively). There were no statistically significant differences in the sociodemographic characteristics between women who were able to use their preferred provider/location and those who were not able to implement their preferred choice, with the exception of state of residence.

Conclusions
These findings provide insights on barriers to abortion care in Nigeria, suggesting discretion is key to many women’s choice of abortion location, while cost and distance prevent many from seeking their preferred care provider/location. Results also highlight the diversity of women’s abortion care preferences in a legally restrictive environment.
A novel upper-limb tracking system in a virtual environment for stroke rehabilitation
Authors: Cha Kuan , Wang Jinying , Li Yan , Shen Longbin , Chen Zhuoming , Long Jinyi 
Published: November 2021

AbstractBackgroundThe transfer of the behaviors of a human’s upper limbs to an avatar is widely used in the field of virtual reality rehabilitation. To perform the transfer, movement tracking technology is required. Traditionally, wearable tracking devices are used for tracking; however, these devices are expensive and cumbersome. Recently, non-wearable upper-limb tracking solutions have been proposed, which are less expensive and more comfortable. However, most products cannot track the upper limbs, including the arms and all the fingers at the same time, which limits the limb parts for tracking in a virtual environment and may lead to a limited rehabilitation effect.MethodsIn this paper, a novel virtual reality rehabilitation system (VRRS) was developed for upper-limb rehabilitation. The VRRS could track the motion of both upper limbs, integrate fine finger motion and the range of motion of the entire arm and map the motion to an avatar. To test the performance of VRRS, two experiments were designed. In the first experiment, we investigated the effect of VRRS on virtual body ownership, agency and location of the body and usability in 8 healthy participants by comparing it with a partial upper-limb tracking method based on a Leap Motion controller (LP) in the same virtual environments. In the second experiment, we examined the feasibility of VRRS in upper-limb rehabilitation with 27 stroke patients.ResultsVRRS improved the users’ senses of body ownership, agency, and location of the body. The users preferred using the VRRS to using the LP. In addition, we found that although the upper limb motor function of patients from all groups was improved, the difference between the FM scores tested on the first day and the last day of the experimental group was more significant than that of the control groups.ConclusionsA VRRS with motion tracking of the upper limbs and avatar control including the arms and all the fingers was developed. It resulted in an improved user experience of embodiment and effectively improved the effects of upper limb rehabilitation in stroke patients.Trial registrationThe study was registered at the First Affiliated Hospital of Jinan University Identifier: KY-2020–036; Date of registration: June 01, 2020.
Detection and phylogenetic analysis of a novel tick-borne virus in Haemaphysalis longicornis ticks and sheep from Shandong, China
Authors: Shao Lijun , Chang Ruiheng , Liu Lin , Wang Yongjin , Gao Yun , Wang Shaoqing , Sun Hengyi , Niu Guoyu 
Published: November 2021

AbstractDabieshan tick virus (DTV) was first identified in Haemaphysalis longicornis from Hubei Province, China in 2015. However, its pathogenic potential to animals and human remains to be further explored. In this study, a total of 170 engorged ticks and 22 sheep serum samples were collected from Taian and Yantai city, Shandong Province to investigate the presence of DTV. The results of qRT-PCR revealed the positive rate of 13.6% (3/22) in sheep serum and 8.2% (14/170) in attached ticks, respectively. Phylogenetic analysis demonstrated a close evolutionary relationship among those DTV isolates from animal and ticks, and DTV might be relatively conservative in evolution. These findings are the first to demonstrate molecular evidence of DTV in domestic animals. Nonetheless, whether or not causing disease in animals, DTV deserves further investigation.
The effect of dietary lipid quality in early life on serum LysoPC(18:2) levels and their association with adult blood glucose levels in intrauterine growth restricted rats
Authors: Kodde Andrea , Mischke Mona , Rakhshandehroo Maryam , Voggel Jenny , Fink Gregor , Nüsken Eva , Rauh Manfred , van der Beek Eline M. , Dötsch Jörg , Nüsken Kai-Dietrich 
Published: November 2021

AbstractBeing born small-for-gestational-age, especially with subsequent catch-up growth, is associated with impaired metabolic health in later-life. We previously showed that a postnatal diet with an adapted lipid droplet structure can ameliorate some of the adverse metabolic consequences in intrauterine growth-restricted (IUGR) rats. The aim of the present work was to explore possible underlying mechanism(s) and potential biomarkers. To this end, serum metabolomics was performed in postnatal day (PN) 42 and PN96 samples of the above-mentioned rat offspring, born after uterine vasculature ligation. Blood samples were collected at PN42, directly after a postnatal dietary intervention with either complex lipid matrix (CLM) or control (CTRL) diet, and at PN96 after a subsequent western-style diet (WSD). Offspring of Non-operated (NOP) dams fed CTRL in early life were included as control group. In the PN42 metabolomics data, 11 co-abundance modules of metabolites were identified, of which four were significantly correlated to adult blood glucose levels at PN96. Further analyses showed that Lysophosphatidylcholine(18:2) (LysoPC(18:2)) levels were reduced by ligation (p < 0.01) and restored in CLM fed animals (p < 0.05). LysoPC(18:2) levels at PN42 correlated inversely with adult blood glucose levels. These data indicate that early-life LysoPC(18:2) blood levels may predict adult blood glucose levels and are affected by a postnatal diet with an adapted lipid droplet structure in IUGR offspring.