bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperactivated Wnt-β-catenin signaling in the absence of sFRP1 and sFRP5 disrupts trophoblast differentiation through repression of Ascl2
Authors: Bao Haili , Liu Dong , Xu Yingchun , Sun Yang , Mu Change , Yu Yongqin , Wang Chunping , Han Qian , Liu Sanmei , Cai Han , Liu Fan , Kong Shuangbo , Deng Wenbo , Cao Bin , Wang Haibin , Wang Qiang , Lu Jinhua
Published: October 2020

Background

Wnt signaling is a critical determinant for the maintenance and differentiation of stem/progenitor cells, including trophoblast stem cells during placental development. Hyperactivation of Wnt signaling has been shown to be associated with human trophoblast diseases. However, little is known about the impact and underlying mechanisms of excessive Wnt signaling during placental trophoblast development.

Results

In the present work, we observed that two inhibitors of Wnt signaling, secreted frizzled-related proteins 1 and 5 (Sfrp1 and Sfrp5), are highly expressed in the extraembryonic trophoblast suggesting possible roles in early placental development. Sfrp1 and Sfrp5 double knockout mice exhibited disturbed trophoblast differentiation in the placental ectoplacental cone (EPC), which contains the precursors of trophoblast giant cells (TGCs) and spongiotrophoblast cells. In addition, we employed mouse models expressing a truncated β-catenin with exon 3 deletion globally and trophoblast-specifically, as well as trophoblast stem cell lines, and unraveled that hyperactivation of canonical Wnt pathway exhausted the trophoblast precursor cells in the EPC, resulting in the overabundance of giant cells at the expense of spongiotrophoblast cells. Further examination uncovered that hyperactivation of canonical Wnt pathway disturbed trophoblast differentiation in the EPC via repressing Ascl2 expression.

Conclusions

Our investigations provide new insights that the homeostasis of canonical Wnt-β-catenin signaling is essential for EPC trophoblast differentiation during placental development, which is of high clinical relevance, since aberrant Wnt signaling is often associated with trophoblast-related diseases.
How important are parents in the development of child anxiety and depression? A genomic analysis of parent-offspring trios in the Norwegian Mother Father and Child Cohort Study (MoBa)
Authors: Cheesman Rosa , Eilertsen Espen Moen , Ahmadzadeh Yasmin I. , Gjerde Line C. , Hannigan Laurie J. , Havdahl Alexandra , Young Alexander I. , Eley Thalia C. , Njølstad Pål R. , Magnus Per , Andreassen Ole A. , Ystrom Eivind , McAdams Tom A.
Published: October 2020

Background

Many studies detect associations between parent behaviour and child symptoms of anxiety and depression. Despite knowledge that anxiety and depression are influenced by a complex interplay of genetic and environmental risk factors, most studies do not account for shared familial genetic risk. Quantitative genetic designs provide a means of controlling for shared genetics, but rely on observed putative exposure variables, and require data from highly specific family structures.

Methods

The intergenerational genomic method, Relatedness Disequilibrium Regression (RDR), indexes environmental effects of parents on child traits using measured genotypes. RDR estimates how much the parent genome influences the child indirectly via the environment, over and above effects of genetic factors acting directly in the child. This ‘genetic nurture’ effect is agnostic to parent phenotype and captures unmeasured heritable parent behaviours. We applied RDR in a sample of 11,598 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) to estimate parental genetic nurture separately from direct child genetic effects on anxiety and depression symptoms at age 8. We tested for mediation of genetic nurture via maternal anxiety and depression symptoms. Results were compared to a complementary non-genomic pedigree model.

Results

Parental genetic nurture explained 14% of the variance in depression symptoms at age 8. Subsequent analyses suggested that maternal anxiety and depression partially mediated this effect. The genetic nurture effect was mirrored by the finding of family environmental influence in our pedigree model. In contrast, variance in anxiety symptoms was not significantly influenced by common genetic variation in children or parents, despite a moderate pedigree heritability.

Conclusions

Genomic methods like RDR represent new opportunities for genetically sensitive family research on complex human traits, which until now has been largely confined to adoption, twin and other pedigree designs. Our results are relevant to debates about the role of parents in the development of anxiety and depression in children, and possibly where to intervene to reduce problems.
Influenza A virus enhances ciliary activity and mucociliary clearance via TLR3 in airway epithelium
Authors: Kamiya Yosuke , Fujisawa Tomoyuki , Katsumata Mineo , Yasui Hideki , Suzuki Yuzo , Karayama Masato , Hozumi Hironao , Furuhashi Kazuki , Enomoto Noriyuki , Nakamura Yutaro , Inui Naoki , Setou Mitsutoshi , Ito Masahiko , Suzuki Tetsuro , Ikegami Koji , Suda Takafumi
Published: October 2020

Background

Viral respiratory tract infections, such as influenza A virus (IAV), are common and life-threatening illnesses worldwide. The mechanisms by which viruses are removed from the respiratory tract are indispensable for airway host defense. Mucociliary clearance is an airway defense mechanism that removes pathogens from the respiratory tract. The coordination and modulation of the ciliary beating of airway epithelial cells play key roles in maintaining effective mucociliary clearance. However, the impact of respiratory virus infection on ciliary activity and mucociliary clearance remains unclear.

Methods

Tracheal samples were taken from wild-type (WT) and Toll-like receptor 3 (TLR3)-knockout (KO) mice. Transient organ culture of murine trachea was performed in the presence or absence of IAV, polyI:C, a synthetic TLR3 ligand, and/or reagents. Subsequently, cilia-driven flow and ciliary motility were analyzed. To evaluate cilia-driven flow, red fluorescent beads were loaded into culture media and movements of the beads onto the tracheal surface were observed using a fluorescence microscope. To evaluate ciliary motility, cilia tips were labeled with Indian ink diluted with culture medium. The motility of ink-labeled cilia tips was recorded by high-speed cameras.

Results

Short-term IAV infection significantly increased cilia-driven flow and ciliary beat frequency (CBF) compared with the control level in WT culture. Whereas IAV infection did not elicit any increases of cilia-driven flow and CBF in TLR3-KO culture, indicating that TLR3 was essential to elicit an increase of cilia-driven flow and CBF in response to IAV infection. TLR3 activation by polyI:C readily induced adenosine triphosphate (ATP) release from the trachea and increases of cilia-driven flow and CBF in WT culture, but not in TLR3-KO culture. Moreover, blockade of purinergic P2 receptors (P2Rs) signaling using P2R antagonist, suramin, suppressed polyI:C-mediated increases of cilia-driven flow and CBF, indicating that TLR3-mediated ciliary activation depended on released extracellular ATP and the autocrine ATP-P2R loop.

Conclusions

IAV infection readily increases ciliary activity and cilia-driven flow via TLR3 activation in the airway epithelium, thereby hastening mucociliary clearance and “sweeping” viruses from the airway as an initial host defense response. Mechanically, extracellular ATP release in response to TLR3 activation promotes ciliary activity through autocrine ATP-P2R loop.
Exosomes containing miRNAs targeting HER2 synthesis and engineered to adhere to HER2 on tumor cells surface exhibit enhanced antitumor activity
Authors: Wang Lei , Zhou Xusha , Zou Weixuan , Wu Yinglin , Zhao Jing , Chen Xiaoqing , Zhou Grace Guoying
Published: October 2020

Background

Exosomes are small, cellular membrane-derived vesicles with a diameter of 50–150 nm. Exosomes are considered ideal drug delivery systems with a wide range of applications in various diseases, including cancer. However, nonspecific delivery of therapeutic agents by exosomes in vivo remains challenging. Human epidermal growth factor receptor 2 (HER2) is an epidermal growth factor receptor tyrosine kinase, and its overexpression is usually associated with cell survival and tumor progression in various cancers. In this study, we aim to develop novel exosomes with dual HER2-targeting ability as a nanoparticle delivery vehicle to enhance antitumor efficacy in vivo.

Results

Here, we report the generation of two kinds of exosomes carrying miRNAs designed to block HER2 synthesis, which consequently showed a distinct anti-tumor effect. The 293-miR-HER2 exosomes package and deliver miRNAs targeting HER2 to recipient cells to block HER2 synthesis. The anti-tumor effect of these exosomes on cancer cells dependent on HER2 for survival but do not affect cells that lack HER2 or that are engineered to express HER2 but are not dependent on it for survival. In contrast, 293-miR-XS-HER2 exosomes carry an additional peptide, which enables them to adhere to HER2 on the surface of cancer cells. Consequently, these exosomes preferentially enter these cells with surface expression of HER2 and further displayed a tumoricidal effect. The 293-miR-XS-HER2 exosomes are significantly more effective than the 293-miR-HER2 exosomes in shrinking HER2-positive tumors implanted in mice.

Conclusions

Collectively, as novel antitumor drug delivery vehicles, HER2 dual-targeting exosomes exhibit increased target-specific delivery efficiency and can be further utilized to develop new nanoparticle-based targeted therapies.
Cerebrospinal fluid analysis in 108 patients with progressive multifocal leukoencephalopathy
Authors: Möhn Nora , Luo Yi , Skripuletz Thomas , Schwenkenbecher Philipp , Ladwig Anne , Warnke Clemens , Meuth Sven G. , Wiendl Heinz , Gross Catharina C. , Schröder Christoph , Haghikia Aiden , Stangel Martin
Published: October 2020

Background

Progressive multifocal leukoencephalopathy (PML) is caused by an opportunistic infection with JC polyoma virus (JCPyV) and mainly affects immunocompromised patients. It leads to pronounced demyelination of the central nervous system (CNS) resulting in severe disability or even death. Detection of JCPyV DNA in the cerebrospinal fluid (CSF) is usually accepted as proof for the diagnosis of PML. Routine CSF parameters, like CSF cell count, protein concentration, Qalbumin, or intrathecal immunoglobulin synthesis are mostly considered normal. However, this has not been investigated systematically.

Methods

We analyzed routine CSF parameters in a cohort of 108 PML patients that were treated at four different neurological centers in Germany. The patients exhibited different underlying conditions with natalizumab-treated multiple sclerosis (n = 54) and human immunodeficiency virus (HIV)-infection (n = 25) being the most frequent. The data were collected at the respective centers in accordance with local requirements and then jointly analyzed. The total PML cohort was compared with a control group of patients with normal pressure hydrocephalus (NPH) and idiopathic intracranial hypertension (IIH). Multiple sclerosis and HIV patients were additionally compared with their own non-PML control groups.

Results

The PML group showed an elevated cell count (p < 0.001) compared to the control group, however, this effect was mainly driven by HIV-PML patients. This subgroup also demonstrated a significantly higher proportion of patients with a disturbed blood-CSF-barrier function.

Conclusions

This comprehensive, retrospective study on CSF diagnostic analysis in PML patients provides insight into the CSF of those patients. It demonstrates that CSF composition in PML patients may be specific for the underlying condition that predisposes for the development of PML and thus data have to be interpreted in this context.
Pattern of cigarette smoking: intensity, cessation, and age of beginning: evidence from a cohort study in West of Iran
Authors: Hamzeh Behrooz , Farnia Vahid , Moradinazar Mehdi , Pasdar Yahya , Shakiba Ebrahim , Najafi Farid , Alikhani Mostafa
Published: October 2020

Background

Smoking is a social epidemic and one of the main risk factors for premature deaths and disabilities worldwide. In the present study, we investigated the Pattern of Cigarette Smoking: intensity, cessation, and age of the beginning.

Methods

Data collected from the recruitment phase of Ravansar (a Kurd region in western Iran) Non-Communicable Disease (RaNCD) cohort study was analyzed by using Chi-square test, univariate and multivariate logistic regressions, Poisson regression, and linear regression.

Results

Totally 10,035 individuals (47.42% males) participated in the study. Mean age was lower for males (47.45 yr) than for females (48.36 yr). Prevalence of smoking was 20% (36.4% of males and 5.23% of females). Compared to female participants, males showed a 7-fold higher prevalence of smoking and started smoking about 4 years earlier. Being married, having a lower BMI, living in rural areas, and being exposed to secondhand smoke (SHS) were predictors of higher smoking prevalence rates. Furthermore, current exposure to SHS, higher smoking intensity, later smoking initiation, male gender, younger age, lower education, and lower BMI were related to lower likelihood of stopping smoking. Heavy smokers began to smoke about 4 years earlier than casual smokers did. Finally, being divorced/ widow/ widower/ single and childhood exposure to SHS were found to increase the likelihood of becoming a smoker.

Conclusions

Based on present research results, health programs specific to smoking cessation should take socio-demographic factors, smoking history, and current smoking behavior into account.
Severity of radiation pneumonitis, from clinical, dosimetric and biological features: a pilot study
Authors: Aso Samantha , Navarro-Martin Arturo , Castillo Richard , Padrones Susana , Castillo Edward , Montes Ana , Martínez José Ignacio , Cubero Noelia , López Rosa , Rodríguez Laura , Palmero Ramon , Manresa Federico , Guerrero Thomas , Molina María
Published: October 2020

Background and objective

Radiation pneumonitis (RP) could be a lethal complication of lung cancer treatment. No reliable predictors of RP severity have been recognized. This prospective pilot study was performed to identify early predictors of high grade lung toxicity and to evaluate clinical, biological or dosimetric features associated with different grades of toxicity.

Method

Sixteen patients with non-small cell lung cancer with indication of concurrent chemoradiotherapy using 60 Gy/2 Gy/fraction starting at cycle one of platinum based chemotherapy were included. Bronchoalveolar lavage (BAL), pulmonary function testing (PFT), and 18F-2-fluoro-2-deoxy-D-glucose positron-emission tomography was performed before radiotherapy (RT), after three weeks of treatment, and two months post-RT. For analysis, patients were grouped by grade (low [G1-G2] vs. high [G3-G5]). The two groups were compared to identify predictors of RP. Protein expression BAL and lung tissue metabolism was evaluated in two patients (RP-G1 vs. RP-G3). Categorical variables such as comorbidities, stages and locations were summarized as percentages. Radiation doses, pulmonary function values and time to RP were summarized by medians with ranges or as means with standard deviation. Longitudinal analysis PFT was performed by a T-test.

Results

All 16 patients developed RP, as follows: G1 (5 pts; 31.3%); G2 (5 pts; 31.3%); G3 (5 pts; 31.3%); and G5 (1 pts; 6.1%). Patients with high grade RP presented significant decrease (p = 0.02) in diffusing lung capacity for carbon monoxide (DLCO) after three weeks of RT. No correlation between dosimetric values and RP grades was observed. BAL analysis of the selected patients showed that CXCL-1, CD154, IL-1ra, IL-23, MIF, PAI-1 and IFN-γ were overexpressed in the lungs of the RP-G3 patient, even before treatment. The pre-RT SUVmax value in the RP-G3 patient was non-significantly higher than in the patient with RP-G1.

Conclusions

RT induces some degree of RP. Our data suggest that decrease in DLCO% is the most sensitive parameter for the early detection of RP. Moreover, we detect biological differences between the two grades of pneumonitis, highlighting the potential value of some cytokines as a prognostic marker for developing high grade lung toxicity. Further multicenter studies with larger sample size are essential to validate these findings.
Heart transplantation of patients with ventricular assist devices: impact of normothermic ex-vivo preservation using organ care system compared with cold storage
Authors: Kaliyev Rymbay , Lesbekov Timur , Bekbossynov Serik , Nurmykhametova Zhuldyz , Bekbossynova Makhabbat , Novikova Svetlana , Medressova Assel , Smagulov Nurlan , Faizov Linar , Samalavicius Robertas , Pya Yuriy
Published: October 2020

Background

Organ Care System (OCS) minimizes the cold ischemic time and allows for optimization of logistics and meticulous recipient preparation. Impact of normothermic ex-vivo preservation using OCS compared with cold storage (CS) for prolonged heart preservation especially beneficial for high-risk recipients bridged to transplantation with Mechanical Circulatory Support (MCS).

Methods

Between 2012 and 2018, we performed a retrospective single-center review of prospectively collected data. All patients who underwent heart transplantation with MCS using the OCS Heart (n = 25) versus standard cold storage (n = 10) were included in this study.

Results

During this period, 353 patients were implanted with left ventricular assisted device (LVAD) and 35 (10%) were bridged to heart transplantation. There was no significant difference in donor and recipient characteristics and risk factors. The Index for Mortality Prediction after Cardiac Transplantation (IMPACT) score was a trend towards higher estimated risk of death at 1y in the OCS group (14.2 vs. 10.8% p = 0.083). Mean total ischemic time during preservation was statistically significantly longer in CS vs OCS group (210 (23) Vs 74.6 (13) min p = 0.001). Median ex vivo normothermic heart perfusion time in OCS was 348.4(132; 955) min. There was significant difference in total out of body time between OCS group 423(67) Vs CS group 210(23) min p = 0.002). All patients were alive on the 30th days post implant in CS groups and 96% in OCS group (p = 0.5).

Conclusion

Normothermic ex-vivo preservation of the allograft during transportation with the organ care system might be beneficial for long-time out of body organ preservation in comparison of cold storage especially for recipients on mechanical circulatory support.
The effect of the glucosylceramide synthase inhibitor lucerastat on cardiac repolarization: results from a thorough QT study in healthy subjects
Authors: Mueller Markus S. , Sidharta Patricia N. , Voors-Pette Christine , Darpo Borje , Xue Hongqi , Dingemanse Jasper
Published: October 2020

Background

Fabry disease is a rare inherited glycosphingolipid storage disorder caused by deleterious mutations in the GLA gene coding for the lysosomal enzyme α-galactosidase A. The glucosylceramide synthase inhibitor lucerastat is an iminosugar with potential to provide oral substrate reduction therapy in Fabry disease, regardless of the patient´s underlying mutation. Since lucerastat exhibits systemic exposure and many patients with Fabry disease suffer from rhythm and conduction abnormalities its effects on cardiac repolarization were evaluated in a thorough QT study.

Methods

In Part A of this randomized, double-blind, placebo-controlled phase 1 study, single oral doses of 2000 and 4000 mg lucerastat were investigated to determine the supratherapeutic dose for Part B. The latter was a four-way crossover study to demonstrate that lucerastat at single oral therapeutic and supratherapeutic doses had no effect on the QTc interval > 10 ms using concentration-QTc modeling as primary analysis. The primary ECG endpoint was placebo-corrected change-from-baseline (ΔΔ) in Fridericia-corrected QTc (ΔΔQTcF). Open-label moxifloxacin served as positive control.

Results

The effect of lucerastat on ΔΔQTcF was predicted as 0.39 ms (90% confidence interval [CI] − 0.13 to 0.90) and 1.69 ms (90% CI 0.33–3.05) at lucerastat peak plasma concentration after dosing with 1000 mg (5.2 µg/mL) and 4000 mg (24.3 µg/mL), respectively. A QTcF effect > 10 ms was excluded up to lucerastat plasma concentrations of approximately 34.0 µg/mL. Lucerastat did not exert an effect on other ECG parameters. Across doses, absorption of lucerastat was rapid, its elimination half-life ranged from 8.0 to 10.0 h, and the pharmacokinetics (PK) of lucerastat were dose-proportional. Moxifloxacin PK were in line with published data and assay sensitivity was demonstrated by the moxifloxacin QTc response. Lucerastat was safe and well tolerated.

Conclusions

Lucerastat up to a dose of 4000 mg has no clinically relevant liability to prolong the QT interval or any clinically relevant effect on other ECG parameters. This will be an important factor in the overall benefit-risk assessment of lucerastat in the potential treatment of Fabry disease.

Trial registration The study was registered with the ClinicalTrials.gov identifier NCT03832452 (February 6th, 2019, https://clinicaltrials.gov/ct2/show/NCT03832452) and the EudraCT number 2018-004546-42 (December 17th, 2018).
Design, development and deployment of a web-based interoperable registry for inherited retinal dystrophies in Portugal: the IRD-PT
Authors: Marques João Pedro , Carvalho Ana Luísa , Henriques José , Murta Joaquim Neto , Saraiva Jorge , Silva Rufino
Published: October 2020

Background

The development of multicenter patient registries promotes the generation of scientific knowledge by using real-world data. A country-wide, web-based registry for inherited retinal dystrophies (IRDs) empowers patients and community organizations, while supporting formal partnerships research. We aim to describe the design, development and deployment of a country-wide, with investigators and stakeholders in the global aim to develop high-value, high-utility web-based, user-friendly and interoperable registry for IRDs—the IRD-PT.

Results

The IRD-PT is a clinical/genetic research registry included in the retina.pt platform (https://www.retina.com.pt), which was developed by the Portuguese Retina Study Group. The retina.pt platform collects data on individuals diagnosed with retinal diseases, from several sites across Portugal, with over 1800 participants and over 30,000 consultations to date. The IRD-PT module interacts with the retina.pt core system which provides a range of basic functions for patient data management, while the IRD-PT module allows data capture for the specific purpose of IRDs. All IRDs are coded accordingly to the International Statistical Classification of Diseases and Related Health Problems (ICD) 9, ICD 10, ICD 11, and Orphanet Rare Disease Ontology (ORPHA codes) to make the IRD-PT interoperable with other IRD registries across the world. Furthermore, the genes are coded according to the Ontology of Genes and Genomes and Online Mendelian Inheritance in Man, whereas signs and symptoms are coded according to the Human Phenotype Ontology. The IRD-PT module pre-launched at Centro Hospitalar e Universitário de Coimbra, the largest reference center for IRDs in Portugal. As of April 1st 2020, finalized data from 537 participants were available for this preliminary analysis.

Conclusions

In the specific field of rare diseases, the use of registries increases research accessibility for individuals, while providing clinicians/investigators with a coherent data ecosystem necessary to boost research. Appropriate design and implementation of patient registries enables rapid decision making and ongoing data mining, ultimately leading to improved patient outcomes. We have described here the principles behind the design, development and deployment of a web-based, user-friendly and interoperable software tool aimed to generate important knowledge and collecting high-quality data on the epidemiology, genomic landscape and natural history of IRDs in Portugal.
Ovarian metastasis from nongynecologic primary sites: a retrospective analysis of 177 cases and 13-year experience
Authors: Zhang Jing-Jing , Cao Dong-Yan , Yang Jia-Xin , Shen Keng
Published: October 2020

Background

Metastasis to the ovary from nongynecologic organs accounts for 9% of all ovarian malignancies. Although the most common nongynecologic primary site of ovarian metastasis is the gastrointestinal tract, metastasis from other sites to the ovary is not uncommon. Differential diagnosis of primary and metastatic ovarian tumors is important; otherwise, appropriate treatment cannot be determined. Furthermore, an optimal treatment strategy for ovarian metastasis from nongynecologic primary sites still needs to be explored.

Methods

One hundred seventy-seven patients with ovarian metastasis from nongynecologic primary sites admitted to Peking Union Medical College Hospital between May 2005 and May 2018 were retrospectively evaluated.

Results

The mean age was 48 years (range, 18–83). Approximately 60% of patients were premenopausal women. The two most common nongynecologic primary sites of ovarian metastasis were the colorectum (68 cases) and stomach (61 cases). In addition to the most common symptoms of abdominal distension (39.0%), abdominal pain (37.9%), and ascites (27.7%), 18.1% of patients presented with abnormal uterine bleeding. Half of the patients who tested serum CA-125 preoperatively had elevated CA-125 levels within the range of 35 U/ml to 200 U/ml. More than 70% of synchronous ovarian metastases were preoperatively misdiagnosed as primary ovarian cancer. Of all included cases, 56.5% achieved optimal cytoreductive surgery (the diameter of the largest residual lesion < 2 cm). The overall 5-year survival rate and median survival time were 10% and 20 months, respectively. The primary site, optimal cytoreductive surgery, tumor differentiation, and postoperative adjuvant treatment were identified as prognostic indicators.

Conclusions

The colorectum and stomach are the most common nongynecologic primary sites of ovarian metastasis. Synchronous ovarian metastasis is easily misdiagnosed as primary ovarian cancer. Optimal cytoreductive surgery and postoperative adjuvant treatment can be performed to confer survival benefit in selected patients.
Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression
Authors: Heng Benjamin , Bilgin Ayse A. , Lovejoy David B. , Tan Vanessa X. , Milioli Heloisa H. , Gluch Laurence , Bustamante Sonia , Sabaretnam Tharani , Moscato Pablo , Lim Chai K. , Guillemin Gilles J.
Published: October 2020

Background

Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanisms to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa.

Methods

To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines and clinical samples (n = 1997) that represent major subtypes of BrCa (luminal, HER2-enriched, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry, and ultra-high pressure liquid chromatography on these samples to quantify the KP enzyme gene, protein, and activity, respectively.

Results

We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression, and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA).

Conclusions

Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.
The effects of exercise training on hypothalamic-pituitary-adrenal axis reactivity and autonomic response to acute stress—a randomized controlled study
Authors: Arvidson Elin , Dahlman Anna Sjörs , Börjesson Mats , Gullstrand Lennart , Jonsdottir Ingibjörg H.
Published: October 2020

Background

Exercise training is suggested to have a stress-buffering effect on physiological reactions to acute stress. The so-called cross-stressor adaptation hypothesis is one of many theories behind the plausible effects, proposing that the attenuated physiological reaction seen in trained individuals in response to acute exercise is also seen when the individual is exposed to acute psychosocial stress. However, few randomized controlled trials (RCT) are available in this field. Therefore, the aim of the present trial was to study the effects of a 6-month aerobic exercise intervention on the physiological response to acute laboratory stress.

Methods

A two-armed RCT including untrained but healthy individuals aged 20–50 years was conducted. Assessments included a peak oxygen uptake test and a psychosocial stress test (the Trier Social Stress Test). A total of 88 participants went through both baseline and follow-up measures (48 in the intervention group and 40 in the control group) with a similar proportion of women and men (20 women and 28 men in the intervention group and 18 women and 22 men in the control group). Outcome measures were adrenocorticotrophic hormone, cortisol, systolic and diastolic blood pressure, and heart rate responses to acute psychosocial stress.

Results

Oxygen uptake and time-to-exhaustion increased significantly following the intervention, while a decrease was seen in the control group. The analyses showed attenuated responses to acute psychosocial stress for all variables in both groups at follow-up, with no differences between the groups. No correlation was seen between amount of exercise training and reactivity to the stress test. Despite the increased oxygen uptake in the intervention group, no differences were seen between the groups for any of the outcome variables at follow-up.

Conclusions

In this study, the cross-stressor adaptation hypothesis could not be confirmed. Both groups showed decreased reactions indicating a habituation to the stress test.

Trial registration

ClinicalTrials.gov NCT02051127. Registered on 31 January 2014—retrospectively registered.
Assessment of the susceptibility status of Aedes aegypti (Diptera: Culicidae) populations to pyriproxyfen and malathion in a nation-wide monitoring of insecticide resistance performed in Brazil from 2017 to 2018
Authors: Campos Kauara Brito , Martins Ademir Jesus , Rodovalho Cynara de Melo , Bellinato Diogo Fernandes , Dias Luciana dos Santos , Macoris Maria de Lourdes da Graça , Andrighetti Maria Teresa Macoris , Lima José Bento Pereira , Obara Marcos Takashi
Published: October 2020

Background

Chemical mosquito control using malathion has been applied in Brazil since 1985. To obtain chemical control effectiveness, vector susceptibility insecticide monitoring is required. This study aimed to describe bioassay standardizations and determine the susceptibility profile of Ae. aegypti populations to malathion and pyriproxyfen, used on a national scale in Brazil between 2017 and 2018, and discuss the observed impacts in arbovirus control.

Methods

The diagnostic-doses (DD) of pyriproxyfen and malathion were determined as the double of adult emergence inhibition (EI) and lethal doses for 99% of the Rockefeller reference strain, respectively. To monitor natural populations, sampling was performed in 132 Brazilian cities, using egg traps. Colonies were raised in the laboratory for one or two generations (F1 or F2) and submitted to susceptibility tests, where larvae were exposed to the pyriproxyfen DD (0.03 µg/l) and adults, to the malathion DD determined in the present study (20 µg), in addition to the one established by the World Health Organization (WHO) DD (50 µg) in a bottle assay. Dose-response (DR) bioassays with pyriproxyfen were performed on populations that did not achieve 98% EI in the DD assays.

Results

Susceptibility alterations to pyriproxyfen were recorded in six (4.5%) Ae. aegypti populations from the states of Bahia and Ceará, with Resistance Ratios (RR95) ranging from 1.51 to 3.58. Concerning malathion, 73 (55.3%) populations distributed throughout the country were resistant when exposed to the local DD 20 µg/bottle. On the other hand, no population was resistant, and only 10 (7.6%) populations in eight states were considered as exhibiting decreased susceptibility (mortality ratios between 90 and 98%) when exposed to the WHO DD (50 µg/bottle).

Conclusions

The feasibility of conducting an insecticide resistance monitoring action on a nation-wide scale was confirmed herein, employing standardized and strongly coordinated sampling methods and laboratory bioassays. Brazilian Ae. aegypti populations exhibiting decreased susceptibility to pyriproxyfen were identified. The local DD for malathion was more sensitive than the WHO DD for early decreased susceptibility detection.
Culex pipiens and Culex restuans egg rafts harbor diverse bacterial communities compared to their midgut tissues
Authors: Juma Elijah O. , Kim Chang-Hyun , Dunlap Christopher , Allan Brian F. , Stone Chris M.
Published: October 2020

Background

The bacterial communities associated with mosquito eggs are an essential component of the mosquito microbiota, yet there are few studies characterizing and comparing the microbiota of mosquito eggs to other host tissues.

Methods

We sampled gravid female Culex pipiens L. and Culex restuans Theobald from the field, allowed them to oviposit in the laboratory, and characterized the bacterial communities associated with their egg rafts and midguts for comparison through MiSeq sequencing of the 16S rRNA gene.

Results

Bacterial richness was higher in egg rafts than in midguts for both species, and higher in Cx pipiens than Cx. restuans. The midgut samples of Cx. pipiens and Cx. restuans were dominated by Providencia. Culex pipiens and Cx. restuans egg rafts samples were dominated by Ralstonia and Novosphingobium, respectively. NMDS ordination based on Bray-Curtis distance matrix revealed that egg-raft samples, or midgut tissues harbored similar bacterial communities regardless of the mosquito species. Within each mosquito species, there was a distinct clustering of bacterial communities between egg raft and midgut tissues.

Conclusion

These findings expand the list of described bacterial communities associated with Cx. pipiens and Cx. restuans and the additional characterization of the egg raft bacterial communities facilitates comparative analysis of mosquito host tissues, providing a basis for future studies seeking to understand any functional role of the bacterial communities in mosquito biology.
Inguinal ureter herniation evaluated with magnetic resonance imaging: a case report
Authors: Renzulli Matteo , Marzocchi Guido , Vara Giulio , Corcioni Beniamino , Ierardi Anna Maria , Gaudiano Caterina , Golfieri Rita
Published: October 2020

Background

The herniation of the ureter into the inguinal canal is a rare condition, but probably underreported. Acquired nephroptosis could cause herniation of the ureter and, therefore, when diagnosed, a full study of the urinary tract should be performed especially in patients with inguinal hernia.

Case presentation

We present the case of an 86-year-old white man with a herniated ureter likely caused by acquired nephroptosis presenting with acute urinary retention, documented with magnetic resonance imaging for the first time.

Conclusions

The Fast Imaging Employing Steady State Acquisition sequence on magnetic resonance imaging, for many reasons, could allow correct evaluation of the urinary tract, especially in cases of renal dysfunction that contraindicate the use of intravenous contrast agents.
RETRACTED ARTICLE: microRNA-375 released from extracellular vesicles of bone marrow mesenchymal stem cells exerts anti-oncogenic effects against cervical cancer
Authors: Ding Feng , Liu Jinhua , Zhang Xiaofei
Published: October 2020

Background

Cervical cancer is the most prevalent gynecological malignancies accompanied by high mortality, where finding a more effective therapeutic option for cervical cancer is necessary. The inhibitory role of microRNAs (miRNAs) derived from the extracellular vesicles (EVs) of the bone marrow mesenchymal stem cells (BMSCs) was analyzed in cervical cancer.

Methods

Expression of miR-375 was examined by RT-qPCR in cervical cancer cell lines. The targeting relation between miR-375 and maternal embryonic leucine zipper kinase (MELK) was predicted by bioinformatics analysis and verified by dual-luciferase reporter gene assay. Isolated BMSCs were transfected with lentivirus-mediated vectors, followed by EV extraction. The morphology of EVs was then identified using a NanoSight particle size analyzer and transmission electron microscope (TEM). The biological properties of cervical cancer cells were evaluated using Transwell, EdU, and TUNEL assays, respectively. Xenograft tumors in nude mice were observed to assess cervical tumorigenesis in vivo.

Results

Low expression of miR-375 and high expression of MELK were detected in cervical cancer samples. MELK was identified as the target gene of miR-375, which was negatively correlated with miR-375 levels. Overexpression of miR-375 suppressed proliferation, migration, and invasion of cervical cancer cells, but enhanced cell apoptosis by cooperating with downregulated MELK expression. miR-375 transferred from BMSC-derived EVs exerted the same effects on cell biological activities. Xenograft assays in vivo proved that miR-375 from BMSC-derived EVs inhibited tumor growth.

Conclusion

The present study highlighted the role of miR-375 from BMSC-derived EVs in suppressing the progression of cervical cancer, which may contribute to the discovery of novel potential biomarkers for cervical cancer therapy.
Global Hopf bifurcation for two zooplankton-phytoplankton model with two delays
Authors: Shi Renxiang , Yang Wenguo
Published: October 2020

In this paper, we study the global existence of a bifurcating periodic solution for a two zooplankton-phytoplankton model with two delays. First, we demonstrate that the bifurcating periodic solution exists when one delay increases and the other delay remains unchanged. Second, we give simulation to describe the bifurcating periodic solution when one delay increases. Our work answers the question in Sect. 5 (Shi and Yu in Chaos Solitons Fractals 100:62–73, 2017).
Using cost-effectiveness analysis to support policy change: varenicline and nicotine replacement therapy for smoking cessation in Jordan
Authors: Madae’en Saba , Obeidat Nour , Adeinat Mohammad
Published: October 2020

Background

Smoking cessation pharmacotherapies (SCPs) have been established as cost-effective for the treatment of tobacco use disorder across a variety of settings. In Jordan, a resource-constrained country where smoking rates rank at one of the highest globally, the cost-effectiveness of SCPs has not yet been quantified. The lack of information about the value of SCPs has contributed to low demand for them (from public and private payers) and consequently low availability of these medications. The aim of this study was to simulate—in a hypothetical cohort of Jordanian smokers—the clinical and economic impact of using two smoking cessation regimens and to generate cost-effectiveness values that can support policy changes to avail smoking cessation medication in a country burdened with heavy tobacco use.

Methods

We employed a similar approach to a widely used economic model, the Benefits of Smoking Cessation on Outcomes (BENESCO) model. A hypothetical cohort of Jordanian male smokers aged 30 to 70 years and making a quit attempt using either a varenicline regimen or a nicotine replacement therapy (NRT) regimen were followed over time (until reaching 70 years of age). Markov simulations were run for the cohort, and life years gained were computed for each arm (compared to no intervention). Drug costs, prevalence of smoking, and population life expectancies were based on Jordanian data. Efficacy data were obtained from the literature. Incremental cost-effectiveness ratios as well as the potential budgetary impact of employing these regimens were generated. Several parameters were modified in sensitivity analyses to capture potential challenges unique to Jordan and that could impact the results.

Results

For a treatment cohort of 527,118 Jordanian male smokers who intended to quit, 103,970 life years were gained using the varenicline regimen, while 64,030 life years were gained using the NRT regimen (compared to the no-intervention arm of life years). The cost per life year gained was JD1204 ($1696 USD) and JD1342 ($1890 USD) for varenicline and NRT, respectively.
Veno-venous ECMO as a platform to evaluate lung lavage and surfactant replacement therapy in an animal model of severe ARDS
Authors: Qaqish Robert , Watanabe Yui , Galasso Marcos , Summers Cara , Ali A adil , Takahashi Mamoru , Gazzalle Anajara , Liu Mingyao , Keshavjee Shaf , Cypel Marcelo , Del Sorbo Lorenzo
Published: October 2020

Background

There are limited therapeutic options directed at the underlying pathological processes in acute respiratory distress syndrome (ARDS). Experimental therapeutic strategies have targeted the protective systems that become deranged in ARDS such as surfactant. Although results of surfactant replacement therapy (SRT) in ARDS have been mixed, questions remain incompletely answered regarding timing and dosing strategies of surfactant. Furthermore, there are only few truly clinically relevant ARDS models in the literature. The primary aim of our study was to create a clinically relevant, reproducible model of severe ARDS requiring extracorporeal membrane oxygenation (ECMO). Secondly, we sought to use this model as a platform to evaluate a bronchoscopic intervention that involved saline lavage and SRT.

Methods

Yorkshire pigs were tracheostomized and cannulated for veno-venous ECMO support, then subsequently given lung injury using gastric juice via bronchoscopy. Animals were randomized post-injury to either receive bronchoscopic saline lavage combined with SRT and recruitment maneuvers (treatment, n = 5) or recruitment maneuvers alone (control, n = 5) during ECMO.

Results

PaO2/FiO2 after aspiration injury was 62.6 ± 8 mmHg and 60.9 ± 9.6 mmHg in the control and treatment group, respectively (p = 0.95) satisfying criteria for severe ARDS. ECMO reversed the severe hypoxemia. After treatment with saline lavage and SRT during ECMO, lung physiologic and hemodynamic parameters were not significantly different between treatment and controls.

Conclusions

A clinically relevant severe ARDS pig model requiring ECMO was established. Bronchoscopic saline lavage and SRT during ECMO did not provide a significant physiologic benefit compared to controls.
Comparison of CAD/CAM manufactured implant-supported crowns with different analyses
Authors: Yeğin Elif , Atala Mustafa Hayati
Published: October 2020

Background

Present study compared the failure load of CAD/CAM-manufactured implant-supported crowns and the stress distribution on the prosthesis-implant-bone complex with different restoration techniques.

Methods

The materials were divided into four groups: group L-M: lithium disilicate ceramic (LDS, monolithic), group L-V: LDS ceramic (veneering), group ZL-M: zirconia-reinforced lithium silicate ceramic (ZLS, monolithic), group ZL-V: ZLS ceramic (veneering). Crown restorations were subjected to load-to-failure test (0.5 mm/min). Failure loads of each group were statistically analyzed (two-way ANOVA, post hoc Tukey HSD, α = 0.05). Finite element analysis (FEA) was used to compare the stress distribution of crown restorations.

Results

Group L-M had the highest failure load (2891.88 ± 410.12 N) with a significant difference from other groups (p < 0.05). Although there was a significant difference between group ZL-M (1750.28 ± 314.96 N) and ZL-V (2202.55 ± 503.14 N), there was no significant difference from group L-V in both groups (2077.37 ± 356.59 N) (p > 0.05).

Conclusions

The veneer application had opposite effects on ceramics, increased the failure load of ZLS and reduced it for LDS without a statistically significant difference. Both materials are suitable for implant-supported crowns. Different restorative materials did not influence the stress distribution, but monolithic restorations reduced the stress concentration on the implant and bone.
Resting-state posterior alpha power changes with prolonged exposure in a natural environment
Authors: Hopman Rachel J. , LoTemplio Sara B. , Scott Emily E. , McKinney Ty L. , Strayer David L.
Published: October 2020

Exposure to environments that contain natural features can benefit mood, cognition, and physiological responses. Previous research proposed exposure to nature restores voluntary attention – attention that is directed towards a task through top down control. Voluntary attention is limited in capacity and depletes with use. Nature provides unique stimuli that do not require voluntary attention; therefore, the neural resources needed for attention to operate efficiently are theorized to restore when spending time in nature. Electroencephalography reflects changes in attention through fluctuations in power within specific frequencies. The current study (N = 29) measured changes in averaged resting state posterior alpha power before, during, and after a multiday nature exposure. Linear mixed-effects models revealed posterior alpha power was significantly lower during the nature exposure compared to pre-trip and post-trip testing, suggesting posterior alpha power may be a potential biomarker for differences related to exposure to natural and urban environments.
Capturing patient experience: does quality-of-life appraisal entail a new class of measurement?
Authors: Schwartz Carolyn E. , Stark Roland B. , Rapkin Bruce D.
Published: October 2020

Background

Two decades of research on quality-of-life (QOL) appraisal have demonstrated links between patient experience and health outcomes and have accounted for both intra-individual change and inter-individual differences in a wide range of research contexts. The present work investigates patterns across diagnostic and demographic groupings to demonstrate how population-specific circumstances drive the structure of QOL appraisal.

Methods

This secondary analysis (N = 6448) utilized data from six patient groups: spine surgery, multiple sclerosis, heterogeneous chronically ill, heterogeneous cancer, bladder cancer, and human immunodeficiency virus (HIV). We explored patterns of inter-item correlation across patient samples, using items from the Standards of Comparison and Sampling of Experience subsections of the QOL Appraisal Profile v1 and v2. Similar matrices were compared by demographic characteristics.

Results

Patterns of inter-item correlations for Standards of Comparison items varied sharply across disease groups and racial groups while being similar across age, gender, and education levels. Inter-item correlation matrices for Sampling of Experience items revealed marked differences among disease groups and educational and racial categories but were similar across age and gender groups.

Conclusions

Appraisal parameters showed evidence of shared and unique aspects across samples and circumstances, findings which make sense in light of sample differences in health status and demographic influences. Tools to assess patient experience and meaning may be best understood asidiometricinstruments. We discuss their distinctions from psychometric and clinimetric tools at theoretical, statistical, and applied levels.