bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship Between the Phenotypes of Circulating Erythrocytes and Cultured Erythroblasts in Paroxysmal Nocturnal Hemoglobinuria
Authors: Shichishima Tsutomu , Saitoh Yurie , Terasawa Takashi , Ogawa Kazuei , Maruyama Yukio
Published: October 2019

To investigate erythropoiesis in paroxysmal nocturnal hemoglobinuria (PNH), we studied the expression of glycosylphosphatidylinositol (GPI)-anchored membrane proteins on circulating erythrocytes and erythroblasts obtained by erythropoietic cell culture in nine patients with this disease. One-color and two-color flow cytometric analyses were performed using monoclonal antibodies for decay-accelerating factor (DAF ) and/or CD59/membrane attack complex-inhibitory factor (MACIF). In addition, terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end-labeling (TUNEL) analysis was performed to assess apoptosis of erythroblasts from six patients. On flow cytometric analysis, cases 1 to 6 had positive and negative erythrocyte populations, case 7 intermediate and negative populations, case 8 positive, intermediate, and negative populations, and case 9 a single double-negative population. In addition, cases 1 to 6 and 8 had positive, intermediate, and negative erythroblast populations, while cases 7 and 9 had intermediate and negative populations. The percentage of double-negative erythrocytes showed a significant correlation with that of double-negative erythroblasts (r = .741, P < .05). In seven of nine patients, more erythroblasts than erythrocytes were negative for the two membrane proteins. Also, some patients with an intermediate population of erythrocytes did not necessarily show an increase of PNH II erythroblasts. Apoptosis of PNH erythroblasts was also detected, but the percentage of apoptotic cells in PNH patients showed no difference from that in healthy volunteers. These findings suggest that the final phenotype of mature erythrocytes in PNH is determined during maturation from erythroblasts to erythrocytes by the disappearance or persistence of PNH II erythroblasts. In addition, PNH erythroblasts in vitro may be partly lost by apoptosis, but apoptosis does not play an important role in determining GPI-linked protein expression.
Role of protein kinase C ζ isoform in Fas resistance of immature myeloid KG1a leukemic cells
Authors: de Thonel Aurélie , Bettaı̈eb Ali , Jean Christine , Laurent Guy , Quillet-Mary Anne
Published: October 2019

Leukemic CD34+ immature acute myeloid leukemia (AML) cells express Fas receptor but are frequently resistant to Fas agonistic reagents. Fas plays an important role in T-cell–mediated cytotoxicity, and recently it has been suggested that altered Fas signaling may contribute to drug resistance. Therefore, Fas resistance could be one of the mechanisms by which AML progenitors escape chemotherapy or T-cell–based immune intervention. However, the molecular mechanism of Fas resistance in AML cells has not been identified. Fas signaling can be interrupted at 3 mains levels: Fas clustering, alteration of death-inducing-signaling-complex (DISC) formation, and effector caspase inhibition of downstream caspase-8. This study shows that in the Fas-resistant CD34+CD38− KG1a cells, Fas agonists resulted in Fas aggregation but not in caspase-8 activation, related to a defect in DISC formation. However, pretreatment with chelerythrin, but not with calphostin C, resulted in the restoration of Fas-induced caspase-8 activation and cytotoxicity, suggesting that some atypical protein kinase C (PKC) isoforms contributed to the lack of DISC formation. Indeed, treatment with antisense oligonucleotides directed against PKCζ and enforced expression of Par-4, a negative regulator of PKCζ activity, restored Fas-induced caspase-8 activity and apoptosis. Moreover, it was found that PKCζ interacts with FADD and that PKCζ immunoextracts prepared from KG1a cells are able to phosphorylate FADD in vitro, whereas this phosphorylation is dramatically reduced in Par-4 transfectant cells. In conclusion, it is suggested that in AML cells, PKCζ plays an important role in Fas resistance by inhibiting DISC formation, possibly by phosphorylating FADD.
High CD123 levels enhance proliferation in response to IL-3, but reduce chemotaxis by downregulating CXCR4 expression
Authors: Wittwer Nicole L. , Brumatti Gabriela , Marchant Ceilidh , Sandow Jarrod J. , Pudney Melanie K. , Dottore Mara , D’Andrea Richard J. , Lopez Angel F. , Ekert Paul G. , Ramshaw Hayley S.
Published: October 2019

Key Points

High CD123 expression increases proliferation and results in enhanced survival in response to low concentration of IL-3 in vitro. High CD123-expressing LSCs downregulate chemokine receptor expression, affecting niche interactions.
Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia
Authors: Cahu Xavier , Calvo Julien , Poglio Sandrine , Prade Nais , Colsch Benoit , Arcangeli Marie-Laure , Leblanc Thierry , Petit Arnaud , Baleydier Frederic , Baruchel Andre , Landman-Parker Judith , Junot Christophe , Larghero Jerome , Ballerini Paola , Delabesse Eric , Uzan Benjamin , Pflumio Francoise
Published: October 2019

Key Points

BM niches differentially support T-ALL. BM niches differentially protect T-ALL cells from chemotherapy.
Immune signatures associated with improved progression-free and overall survival for myeloma patients treated with AHSCT
Authors: Ho Christine M. , McCarthy Philip L. , Wallace Paul K. , Zhang Yali , Fora Ahmad , Mellors Patrick , Tario Joseph D. , McCarthy Benjamin L. S. , Chen George L. , Holstein Sarah A. , Balderman Sophia R. , Cao Xuefang , Paiva Bruno , Hahn Theresa
Published: October 2019

Key Points

Specific immune phenotypes were predictive of long-term survival for MM patients undergoing transplantation. MRD status and use of maintenance therapy were associated with unique immune profiles predictive of outcome.
Mature lymphoid malignancies: origin, stem cells, and chronicity
Authors: Husby Simon , Grønbæk Kirsten
Published: October 2019

The chronic behavior of mature lymphoid malignancies, with relapses occurring years apart in many patients, has until recently been unexplained. Patterns of relapse also differ vastly between disease entities, with some being highly curable by chemotherapy whereas others are destined to reemerge after treatment. Lately, the use of next-generation sequencing techniques has revealed essential information on the clonal evolution of lymphoid malignancies. Also, experimental xenograft transplantation point to the possible existence of an ancestral (stem) cell. Such a malignant lymphoid stem cell population could potentially evade current therapies and be the cause of chronicity and death in lymphoma patients; however, the evidence is divergent across disease entities and between studies. In this review we present an overview of genetic studies, case reports, and experimental evidence of the source of mature lymphoid malignancy and discuss the perspectives.
Allogeneic bone marrow transplant in the absence of cytoreductive conditioning rescues mice with β-thalassemia major
Authors: Huo Yongliang , Lockhart Jonathan R. , Liu Shanrun , Fontenard Suean , Berlett Mike , Ryan Thomas M.
Published: October 2019

Key Points

After completion of the fetal-to-adult globin gene switch, humanized β-thalassemia major mice are transfusion dependent. Perinatal humanized β-thalassemia major mice are rescued by bone marrow transplantation in the absence of cytoreductive conditioning.
Impact of genomic alterations on outcomes in myelofibrosis patients undergoing JAK1/2 inhibitor therapy
Authors: Spiegel Jay Y. , McNamara Caroline , Kennedy James A. , Panzarella Tony , Arruda Andrea , Stockley Tracy , Sukhai Mahadeo , Thomas Mariam , Bartoszko Justyna , Ho Jenny , Siddiq Nancy , Maze Dawn , Schimmer Aaron , Schuh Andre , Sibai Hassan , Yee Karen , Claudio Jamie , Devlin Rebecca , Minden Mark D. , Kamel-Reid Suzanne , Gupta Vikas
Published: October 2019

Key Points

ASXL1/EZH2, transfusion dependence, and a high prognostic risk score predict shorter TTF in MF patients on JAK1/2 inhibitors. These clinical and genetic factors were also associated with decreased overall survival.
TLR2 agonism reverses chemotherapy-induced neutropenia in Macaca fascicularis
Authors: Laping Nicholas J. , DeMartino Michael P. , Cottom Joshua E. , Axten Jeffrey M. , Emery John G. , Guss Jeffrey H. , Burman Miriam , Foley James J. , Cheung Mui , Oliff Allen , Kumar Sanjay
Published: October 2019

Key Points

A novel TLR2 agonist was identified that stimulates the release of G-CSF, IL-6, and monocyte chemoattractant protein 1. This agonist increases neutrophil numbers in a primate model of neutropenia.
Early progression of disease as a predictor of survival in chronic lymphocytic leukemia
Authors: Ahn Inhye E. , Farber Charles M. , Davids Matthew S. , Grinblatt David L. , Kay Neil E. , Lamanna Nicole , Mato Anthony , Nabhan Chadi , Kiselev Pavel , Swern Arlene S. , Flick E. Dawn , Sullivan Kristen , Sharman Jeff P. , Flowers Christopher R.
Published: October 2019

Key Points

Early progression of disease within 2 years of initial therapy independently predicts inferior survival in CLL. Early progression of disease is a robust clinical end point and a useful posttreatment risk stratification tool.
Cytogenetics-based risk prediction of blastic transformation of chronic myeloid leukemia in the era of TKI therapy
Authors: Gong Zimu , Medeiros L. Jeffrey , Cortes Jorge E. , Chen Zi , Zheng Lan , Li Yan , Bai Shi , Lin Pei , Miranda Roberto N. , Jorgensen Jeffrey L. , McDonnell Timothy J. , Wang Wei , Kantarjian Hagop M. , Hu Shimin
Published: October 2019

Key Points

CML patients can be stratified into 4 subgroups with different risk of blastic transformation based on cytogenetic abnormalities. TKI therapy mitigates risk of blastic transformation associated with low-risk ACAs or no ACAs but not that associated with HR ACAs.
Maintenance of telomere length in AML
Authors: Lansdorp Peter M.
Published: October 2019

The importance of telomere length to human health, aging, and cancer continues to be underappreciated. This review examines some basics of telomere biology and relates how telomere function, telomerase activity, and mutations in TERC or TERT are involved in bone marrow failure, leukemias, and other cancers. Given the challenge to obtain accurate data on telomerase activity and telomere length in specific cell types, the situation in acute myeloid leukemia (AML) remains puzzling. In most cancers, telomerase levels are increased after cells have encountered a “telomere crisis,” which is typically associated with poor prognosis. Cells emerging from “telomere crisis” have defective DNA damage responses, resulting, for example, from loss of p53. Such cells often express elevated telomerase levels as a result of point mutations in the TERT promoter or amplification of the TERT gene. While telomeres in AML blasts are typically shorter than expected for normal leukocytes, most AML cells do not show evidence of having gone through a “telomere crisis.” In chronic myeloid leukemia (CML), the difference between the telomere length in nonmalignant T cells and malignant blasts from the same patient was found to correlate with the remaining duration of the chronic phase. This observation supports that a mitotic clock is ticking in CML stem cells and that disease progression in CML heralds the onset of a “telomere crisis.” The presence of very short telomeres in tumor cells was found to predict disease progression in chronic lymphocytic leukemia, myeloma, and various solid tumors. In view of these findings longitudinal studies of telomere length in AML appear worthwhile.
A B-cell–associated gene signature classification of diffuse large B-cell lymphoma by NanoString technology
Authors: Michaelsen Thomas Yssing , Richter Julia , Brøndum Rasmus Froberg , Klapper Wolfram , Johnsen Hans Erik , Albertsen Mads , Dybkær Karen , Bøgsted Martin
Published: October 2019

Key Points

A gene expression assay that accurately assigns B-cell–associated gene signatures to DLBCL with prognostic impact. Robust performance irrespective of sample preparation method and GEP platform.
Prevalence and associated factors for needlestick and sharp injuries (NSIs) among dental assistants in Jeddah, Saudi Arabia
Authors: AlDakhil Lama , Yenugadhati Nagarajkumar , Al-Seraihi Ohoud , Al-Zoughool Mustafa
Published: October 2019

Background

Dental personnel are subject to exposure to a number of occupational factors including needlestick and sharp injuries (NSIs). Our study aims to address knowledge gaps on prevalence and associated factors for needlestick and sharp injuries (NSIs) for the first time in Saudi Arabia.

Methods

This cross-sectional study was conducted on a sample of 450 dental assistants recruited from 40 randomly selected private clinics in Jeddah, Saudi Arabia. Data on demographic characteristics, history of NSIs, nature of work, compliance with infection control protocols, and knowledge of infection control procedures and disease transmission were collected using a self-administered questionnaire. Logistic regression analysis was used to assess factors associated with NSIs; unadjusted and adjusted odds ratios (aORs) and their respective 95% confidence intervals (CIs) were computed.

Results

About three in ten dental assistants experienced at least one NSI (29.8%, 95% CI 25.6–34.2%) in private dental clinics. Lack of adequate knowledge of infection control procedures and disease transmission, non-compliance with infection control protocol of vaccination against hepatitis B virus, and attending 12 or less number of patients daily were significantly associated with increased risk of NSIs (p ≤ 0.05); adjusted odds ratios (95% CI) were 1.87 (1.18–2.97), 1.89 (1.05–3.41), and 1.63 (1.03–2.56), respectively. In addition, dental assistants working in 45.8% of dental clinics that had no infection control unit were positively associated with higher NSI risk (aOR = 2.28, 95% CI 1.45–3.57).

Conclusion

Our study reported the prevalent nature of NSIs among dental assistants in Saudi Arabia and identified key factors that could be targeted to mitigate this preventable condition. Dental assistants would benefit from proper training on infection control protocols and procedures.
Moss species-specific accumulation of atmospheric deposition?
Authors: Schröder Winfried , Nickel Stefan
Published: October 2019

Background

This article presents statistical analyses of elements concentrations in mosses collected in two monitoring programmes: 1. The German moss monitoring as part of the European Moss Survey conducted in 1990, 1995, 2000, 2005 and 2015 at 592, 1026, 1028, 726 and 400 sites across Germany, respectively, and chemically analysed according to harmonised methods throughout Europe; and 2. The moss surveys additionally performed throughout Bavaria, federal state of Germany. The evaluations of the present study are intended to examine indications whether the element accumulations are specific to moss species and whether, therefore, conversion factors should be used. Such observations and recommendations have so far been limited to spatially confined areas and relatively few moss samples and were derived from different studies without a common methodology. Therefore, the objective of this investigation was to analyse large and long-term datasets from moss surveys for differences in element concentrations in different moss species. This analysis was based on data derived from several moss species collected across Germany and specimens of only one moss species collected in the monitoring programme performed by the environmental authority of Bavaria. So far, the presented investigation is the most comprehensive one in terms of running time, spatial density of the measurement network and method harmonisation.

Results

The present study does neither verify nor falsify the hypothesis of moss species-specific element accumulations in mosses. This, like the other studies, is not possible because of its empirical design, since that would require strictly controlled laboratory experiments. However, this investigation yielded hints, that the differences in element accumulation in several moss species across German surveys between 1990 and 2015 are in the range of the intra- and inter-specific variance reported.

Conclusion

It is, therefore, advisable to continue dispensing with conversion factors so far.
Benchmark datasets of immune receptor-epitope structural complexes
Authors: Mahajan Swapnil , Yan Zhen , Jespersen Martin Closter , Jensen Kamilla Kjærgaard , Marcatili Paolo , Nielsen Morten , Sette Alessandro , Peters Bjoern
Published: October 2019

Background

The development of accurate epitope prediction tools is important in facilitating disease diagnostics, treatment and vaccine development. The advent of new approaches making use of antibody and TCR sequence information to predict receptor-specific epitopes have the potential to transform the epitope prediction field. Development and validation of these new generation of epitope prediction methods would benefit from regularly updated high-quality receptor-antigen complex datasets.

Results

To address the need for high-quality datasets to benchmark performance of these new generation of receptor-specific epitope prediction tools, a webserver called SCEptRe (Structural Complexes of Epitope-Receptor) was created. SCEptRe extracts weekly updated 3D complexes of antibody-antigen, TCR-pMHC and MHC-ligand from the Immune Epitope Database and clusters them based on antigen, receptor and epitope features to generate benchmark datasets. SCEptRe also provides annotated information such as CDR sequences and VDJ genes on the receptors. Users can generate custom datasets based by selecting thresholds for structural quality and clustering parameters (e.g. resolution, R-free factor, antigen or epitope sequence identity) based on their need.

Conclusions

SCEptRe provides weekly updated, user-customized comprehensive benchmark datasets of immune receptor-epitope structural complexes. These datasets can be used to develop and benchmark performance of receptor-specific epitope prediction tools in the future. SCEptRe is freely accessible athttp://tools.iedb.org/sceptre.
Interleukin-6 mediates resistance to PI3K-pathway–targeted therapy in lymphoma
Authors: Kim Joo Hyun , Kim Won Seog , Park Chaehwa
Published: October 2019

Background

The phosphoinositol 3-kinase (PI3K) pathway is associated with poor prognosis of hematologic malignancies, providing a strong rationale for the use of PI3K inhibitors in the treatment of malignant lymphoma. However, development of resistance limits the use of PI3K inhibitors in lymphoma patients.

Methods

We established copanlisib (pan-PI3K inhibitor)-resistant B-cell lymphoma and duvelisib (PI3Kδ and -γ inhibitor)-resistant T-cell lymphoma cell lines. The cytokine array and the phospho-kinase array were used to identify up-regulated proteins in the resistant cells. Cytokine expression and phospho-kinase levels were examined by ELISA and Western blot analysis, respectively. Cell proliferation capabilities were measured by using CCK-8 kit and colony formation assay. The effects of inhibitors on apoptosis were detected using an Annexin V-FITC Apoptosis Detection Kit and a flow cytometry system. The underlying mechanisms were studied by transfecting recombinant plasmids or siRNA into lymphoma cell lines. Cells were transiently transfected using the Amaxa electroporation system. We evaluated the effects of PI3K inhibitor alone and in combination with JAK inhibitor (BSK805) on lymphoma proliferation and signaling pathway activation.

Results

Cytokine arrays revealed upregulation of interleukin (IL)-6 in both copanlisib- and duvelisib-resistant cell lines. Phosphorylated STAT5, AKT, p70S6K and MAPK were increased in copanlisib-resistant B-cell lymphoma cells, whereas phosphorylated STAT3 and NF-κB were increased in duvelisib-resistant T cell lymphoma cells. Conversely, depletion of IL-6 sensitized both resistant cell lines, and led to downregulation of phosphorylated STAT3 and STAT5 in copanlisib- and duvelisib-resistant cells, respectively. Moreover, combined treatment with a JAK inhibitor (BSK805) and a PI3K inhibitor circumvented the acquired resistance to PI3K inhibitors in lymphoma, and concurrent inhibition of the activated pathways produced combined effects.

Conclusions

IL-6–induced STAT3 or STAT5 activation is a critical mechanism underlying PI3K inhibitor resistance in lymphoma, supporting the utility of IL-6 as an effective biomarker to predict therapeutic response to PI3K inhibitors.
Maternal cardiometabolic markers are associated with fetal growth: a secondary exploratory analysis of the LIMIT randomised trial
Authors: O’Brien Cecelia M. , Louise Jennie , Deussen Andrea , Dodd Jodie M.
Published: October 2019

Background

To determine the association between maternal cardiometabolic and inflammatory markers with measures of fetal biometry and adiposity.

Methods

Women included in this exploratory analysis were randomised to the ‘Standard Care’ group (N = 911) from the LIMIT randomised trial involving a total of 2212 pregnant women who were overweight or obese (ACTRN12607000161426, Date of registration 9/03/2007, prospectively registered). Fetal biometry including abdominal circumference (AC), estimated fetal weight (EFW), and adiposity measurements (mid-thigh fat mass, subscapular fat mass, abdominal fat mass) were obtained from ultrasound assessments at 28 and 36 weeks’ gestation. Maternal markers included C reactive protein (CRP), leptin and adiponectin concentrations, measured at 28 and 36 weeks’ gestation and fasting triglycerides and glucose concentrations measured at 28 weeks’ gestation.

Results

There were negative associations identified between maternal serum adiponectin and fetal ultrasound markers of biometry and adiposity. After adjusting for confounders, a 1-unit increase in log Adiponectin was associated with a reduction in the mean AC z score [− 0.21 (− 0.35, − 0.07), P = 0.004] and EFW [− 0.23 (− 0.37, − 0.10), P < 0.001] at 28 weeks gestation. Similarly, a 1-unit increase in log Adiponectin was association with a reduction in the mean AC z score [− 0.30 (− 0.46, − 0.13), P < 0.001] and EFW [− 0.24 (− 0.38, − 0.10), P < 0.001] at 36 weeks gestation. There were no consistent associations between maternal cardiometabolic and inflammatory markers with measurements of fetal adiposity.

Conclusion

Adiponectin concentrations are associated with measures of fetal growth. Our findings contribute to further understanding of fetal growth in the setting of women who are overweight or obesity.
EQUIP Emergency: study protocol for an organizational intervention to promote equity in health care
Authors: Varcoe Colleen , Bungay Vicky , Browne Annette J. , Wilson Erin , Wathen C. Nadine , Kolar Kat , Perrin Nancy , Comber Scott , Blanchet Garneau Amélie , Byres David , Black Agnes , Price Elder Roberta
Published: October 2019

Background

Social inequities are widening globally, contributing to growing health and health care inequities. Health inequities are unjust differences in health and well-being between and within groups of people caused by socially structured, and thus avoidable, marginalizing conditions such as poverty and systemic racism. In Canada, such conditions disproportionately affect Indigenous persons, racialized newcomers, those with mental health and substance use issues, and those experiencing interpersonal violence. Despite calls to enhance equity in health care to contribute to improving population health, few studies examine how to achieve equity at the point of care, and the impacts of doing so. Many people facing marginalizing conditions experience inadequate and inequitable treatment in emergency departments (EDs), which makes people less likely to access care, paradoxically resulting in reliance on EDs through delays to care and repeat visits, interfering with effective care delivery and increasing human and financial costs. EDs are key settings with potential for mitigating the impacts of structural conditions and barriers to care linked to health inequities.

Methods

EQUIP is an organizational intervention to promote equity. Building on promising research in primary health care, we are adapting EQUIP to emergency departments, and testing its impact at three geographically and demographically diverse EDs in one Canadian province. A mixed methods multisite design will examine changes in key outcomes including: a) a longitudinal analysis of change over time based on structured assessments of patients and staff, b) an interrupted time series design of administrative data (i.e., staff sick leave, patients who leave without care being completed), c) a process evaluation to assess how the intervention was implemented and the contextual features of the environment and process that are influential for successful implementation, and d) a cost-benefit analysis.

Discussion

This project will generate both process- and outcome-based evidence to improve the provision of equity-oriented health care in emergency departments, particularly targeting groups known to be at greatest risk for experiencing the negative impacts of health and health care inequities. The main deliverable is a health equity-enhancing framework, including implementable, measurable interventions, tested, refined and relevant to diverse EDs.

Trial registration

Clinical Trials.gov #NCT03369678 (registration date November 18, 2017).
Transcriptomic and functional analysis of the oosome, a unique form of germ plasm in the wasp Nasonia vitripennis
Authors: Quan Honghu , Arsala Deanna , Lynch Jeremy A.
Published: October 2019

Background

The oosome is the germline determinant in the waspNasonia vitripennisand is homologous to the polar granules ofDrosophila. Despite a common evolutionary origin and developmental role, the oosome is morphologically quite distinct from polar granules. It is a solid sphere that migrates within the cytoplasm before budding out and forming pole cells.

Results

To gain an understanding of both the molecular basis of oosome development and the conserved essential features of germ plasm, we quantified and compared transcript levels between embryo fragments that contained the oosome and those that did not. The identity of the differentially localized transcripts indicated thatNasoniauses a distinct set of molecules to carry out conserved germ plasm functions. In addition, functional testing of a sample of localized transcripts revealed potentially novel mechanisms of ribonucleoprotein assembly and pole cell cellularization in the wasp.

Conclusions

Our results demonstrate that the composition of germ plasm varies significantly within Holometabola, as very few mRNAs share localization to the oosome and polar granules. Some of this variability appears to be related to the unique properties of the oosome relative to the polar granules inDrosophila, and some may be related to differences in pole formation between species. This work will serve as the basis for further investigation into the patterns of germline determinant evolution among insects, the molecular basis of the unique properties of the oosome, and the incorporation of novel components into developmental networks.
LncRNA PVT1 up-regulation is a poor prognosticator and serves as a therapeutic target in esophageal adenocarcinoma
Authors: Xu Yan , Li Yuan , Jin Jiankang , Han Guangchun , Sun Chengcao , Pizzi Melissa Pool , Huo Longfei , Scott Ailing , Wang Ying , Ma Lang , Lee Jeffrey H. , Bhutani Manoop S. , Weston Brian , Vellano Christopher , Yang Liuqing , Lin Chunru , Kim Youngsoo , MacLeod A. Robert , Wang Linghua , Wang Zhenning , Song Shumei , Ajani Jaffer A.
Published: October 2019

Background

PVT1 has emerged as an oncogene in many tumor types. However, its role in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) is unknown. The aim of this study was to assess the role of PVT1 in BE/EAC progression and uncover its therapeutic value against EAC.

Methods

PVT1 expression was assessed by qPCR in normal, BE, and EAC tissues and statistical analysis was performed to determine the association of PVT1 expression and EAC (stage, metastases, and survival). PVT1 antisense oligonucleotides (ASOs) were tested for their antitumor activity in vitro and in vivo.

Results

PVT1 expression was up-regulated in EACs compared with paired BEs, and normal esophageal tissues. High expression of PVT1 was associated with poor differentiation, lymph node metastases, and shorter survival. Effective knockdown of PVT1 in EAC cells using PVT1 ASOs resulted in decreased cell proliferation, invasion, colony formation, tumor sphere formation, and reduced proportion of ALDH1A1+ cells. Mechanistically, we discovered mutual regulation of PVT1 and YAP1 in EAC cells. Inhibition of PVT1 by PVT1 ASOs suppressed YAP1 expression through increased phosphor-LATS1and phosphor-YAP1 while knockout of YAP1 in EAC cells significantly suppressed PVT1 levels indicating a positive regulation of PVT1 by YAP1. Most importantly, we found that targeting both PVT1 and YAP1 using their specific ASOs led to better antitumor activity in vitro and in vivo.

Conclusions

Our results provide strong evidence that PVT1 confers an aggressive phenotype to EAC and is a poor prognosticator. Combined targeting of PVT1 and YAP1 provided the highest therapeutic index and represents a novel therapeutic strategy.
Potential excess of vaginal examinations during the management of labor: frequency and associated factors in 13 Peruvian hospitals
Authors: Zafra-Tanaka Jessica Hanae , Montesinos-Segura Renee , Flores-Gonzales Pamela D. , Taype-Rondan Alvaro
Published: October 2019

Background

A high number of vaginal examinations (VEs) may lead to a higher risk of infections, as well as discomfort/dissatisfaction with intrapartum care.

Objective

To determine the frequency of potential excess of vaginal examinations (PEVE) during the management of labor and identify its associated factors, in Peruvian hospitals.

Methods

Secondary analysis of the data collected in theDisrespEct and abuse during ChIlDbirth in pEru (DECIDE)study, held between April and May 2016. In this study, women hospitalized in Peruvian hospitals right after giving birth were surveyed by trained personnel. PEVE, the main outcome, was considered as five or more vaginal examinations (VEs) performed during the management of labor. Poisson regression models with robust variance were performed to calculate crude and adjusted prevalence ratios (cPR and aPR) as well as their 95% confidence intervals (95% CI).

Results

One thousand four hundred twenty registries of 13 hospitals from 8 Peruvian cities were evaluated. The number of women studied at each hospital ranged between 100 and 129. The median age was 26 years (interquartile rank: 22–31). The median number of VEs was 3 (interquartile rank: 2–5). The proportion of women who underwent PEVE was 33.9%, this ranged from 0.9 to 69.9% at the studied hospitals. The frequency of PEVE was higher in women who attended > 2 obstetric psychoprophylaxis sessions, compared to those who attended ≤ 2 sessions (aPR: 1.78 95% CI: 1.01–3.12); and among women who gave birth between 18:00 h and 23:59 h, compared to those who did it between 7:00 and 17:59 h (aPR: 1.28 95% CI: 1.04–1.57).

Conclusion

Around one in three women underwent a PEVE, although this frequency varied widely across the evaluated hospitals. Women with more psychoprophylaxis sessions, and who gave birth between 18:00 h and 23:59 h, had a higher PEVE frequency. Future studies should assess in depth the causes and consequences of this high frequency.
Elevated expression of mcl-1 inhibits apoptosis and predicts poor prognosis in patients with surgically resected non-small cell lung cancer
Authors: Wen Qiuyuan , Zhan Yuting , Zheng Hongmei , Zang Hongjing , Luo Jiadi , Zhang Yuting , Wang Weiyuan , Feng Juan , Lu Junmi , Chen Lingjiao , Fan Songqing
Published: October 2019

Background

Mcl-1, an anti-apoptotic member of bcl-2 family, together with cleaved poly (ADC-ribose) polymerase (c-PARP) can serve as a marker of cell apoptosis. Previously we reported that treatment of Mnk inhibitor CGP57380 resulted in decreased Mcl-1 expression while increased c-PARP expression in non-small cell lung cancer (NSCLC) cells. In this study, we aimed to investigate association between Mcl-1 expression and clinicopathological features of NSCLC, and their correlation between Mcl-1 and both proliferation index (PI) and apoptotic index (AI) in NSCLC patients.

Methods

Tissue microarrays (TMA) including 350 cases of surgically resected NSCLC were utilize and stained with Mcl-1, Ki-67 and c-PARP antibodies, PI and AI were then evaluated, respectively.

Results

Higher Mcl-1 expression and PI were observed in NSCLC compared with non-cancerous lung tissues (non-CLT), while AI was significantly lower in lung adenocarcinoma (ADC) compared with non-CLT. Additionally, Mcl-1 expression in lung ADC was evidently higher than that of in lung squamous cell carcinoma (SCC). The elevated Mcl-1 expression was associated with PI, and inversely related to AI in NSCLC. NSCLC patients with elevated Mcl-1 expression and high PI, or with high Mcl-1 expression and low AI had remarkably shorter overall survival time than these patients with low Mcl-1 expression.

Conclusions

Elevated expression of Mcl-1 might be inversely proportional to disease progression of NSCLC patients by promoting cell proliferation and inhibiting apoptosis, and Mcl-1 might serve as novel biomarker of poor prognosis for NSCLC patients.
Validation of revision data for total hip and knee replacements undertaken at a high volume orthopaedic centre against data held on the National Joint Registry
Authors: Afzal Irrum , Radha Sarkhell , Smoljanović Tomislav , Stafford Giles H. , Twyman Roy , Field Richard E.
Published: October 2019

Background

With over 2.35 million records, the National Joint Registry (NJR) is the largest arthroplasty registry in the world. It provides a powerful tool to monitor implant survivorship and influence different surgical strategies. To date, little work has been undertaken to investigate the validity of the ‘Reason for Revision’ recorded in Consultant Outcome Reports on the NJR.

Methods

The NJR was queried to identify all revisions on the THR performed at a single centre over an 11-year period. Review and validation of ‘Reason for Revision’ for each case was undertaken using radiological imaging studies, pathology, histology, microbiology and electronic medical records.

Results

Of the 22,046 primary total hip replacements (THR) and total knee replacements (TKR) undertaken by 23 surgeons at our hospital, over an 11-year period, 1.35% (297) were subsequently reported to the NJR as revised. Discrepancies in reporting to the NJR were identified for 41 cases (25.63%) for THR and 28 (20.40%) cases for TKR. Revision for infection was under-reported for both THR and TKR by 1.88% and 3.65% respectively. Reporting of adverse soft tissue reaction to particulate debris for THR was unreported by 11%. Progressive arthritis following a TKR was unreported by 6.56%. All the cases reported as ‘other’ (8.75% for THRs and 3.65% for TKRs) were reclassified to the most appropriate ‘reason for revision’ category. The ‘reason for revision’ data is recorded to the NJR with findings at the time of surgery. It is some days before microbiology and histology reports become available and source data is not always updated.

Conclusion

If an average of 23% wrong data entry at a highly organised institution is replicated throughout the UK, a formal process to validate primary and revision data submitted to the NJR should be considered. Local scrutiny, review and validation of revision data are all vital to optimise the value of the NJR. Accurate data recorded to the NJR is imperative to provide safe and effective improvements in orthopaedic surgery.
Emodin promotes fibroblast apoptosis and prevents epidural fibrosis through PERK pathway in rats
Authors: Xiong Guirun , Chen Hui , Wan Qi , Dai Jihang , Sun Yu , Wang Jingcheng , Li Xiaolei
Published: October 2019

Background

Laminectomy is usually classed as a common orthopedic surgery, but postoperative epidural fibrosis often leads to less-than-desirable clinical outcomes. As demonstrated by prior studies, emodin (EMO) exerts an anti-fibrotic effect. Here, we carried out investigation into the inhibitory effect created by EMO application on epidural fibrosis after laminectomy in rats.

Methods

The paper conducts a series of experiment. In vitro, we observed the effect of EMO on fibroblasts by Cell Counting Kit-8 (CCK-8) assay. Apoptosis of fibroblasts induced by EMO was detected by western blot, TUNEL assay, and flow cytometry. The results revealed that EMO was capable of inducing fibroblast apoptosis, and the proteins of PERK pathway also changed accordingly. In vivo, the effect of EMO on epidural fibrosis in 12 male Sprague-Dawley rats was observed by histological staining.

Results

CCK-8 assay indicated that EMO was effective in reducing fibroblast viability in a time- and a dose-dependent manner. TUNEL assay and flow cytometry analysis have demonstrated that the apoptotic rate of fibroblasts increased as the EMO concentration rose. Western blot analysis proved that EMO promoted the relative expression of p-perk and p-eIF2α and that the expression of its downstream proteins CHOP and GRP78 was also enhanced. The expression of apoptotic protein Bax and cleaved PARP was upregulated, whereas the expression of anti-apoptotic protein Bcl-2 was downregulated. In addition, histological and immunohistochemical analysis demonstrated that EMO functioned to inhibit epidural fibrosis and increase GRP78 expression in fibrous tissue by promoting apoptosis of fibroblasts.

Conclusions

EMO could have inhibitory effect on epidural fibrosis in a concentration-dependent manner. The potential mechanism might be through PERK signaling pathway to promote fibroblast apoptosis. It has a possibility to be taken as a novel method for the treatment of epidural fibrosis.
“With every passing day I feel like a candle, melting little by little.” experiences of long-term displacement amongst Syrian refugees in Shatila, Lebanon
Authors: Syam Hanadi , Venables Emilie , Sousse Bernard , Severy Nathalie , Saavedra Luz , Kazour Francois
Published: October 2019

Background

Long term displacement and exposure to challenging living conditions can influence family dynamics; gender roles; violence at home and in the community and mental well-being. This qualitative study explores these issues as perceived by Syrian refugees who have been living in Shatila, a Palestinian camp in South Beirut, Lebanon, for at least 2 years.

Methods

Twenty eight in-depth interviews with men and women were conducted between February and June 2018. Women were recipients of mental health services, and men were recruited from the local community. Interviews were conducted in Arabic, translated, transcribed, coded and analysed using thematic content analysis.

Results

Our results show patterns of harsh living conditions similar to those described earlier in the course of the Syrian refugee crisis. Lack of infrastructure, overcrowding, cramped rooms and violence were all reported. Participants also described a lack of social support, discrimination and harassment within the host community, as well as limited social support networks within their own Syrian refugee community. Family dynamics were affected by the increased responsibilities on men, women and children; with additional economic and employment demands on men, women assuming the roles of ‘mother and father’ and children having to work and contribute to the household. Participants discussed several types of violence, including parental violence against children and violence in the community. Violence against women was also reported. Reported mental health issues included depression, anxiety, sadness, frustration, hopelessness, self-neglect and a loss of sense of self and self-worth. Some participants expressed a wish to die.

Conclusions

This study describes experiences of changing gender roles, family dynamics, violence and mental health after long-term displacement in in Shatila camp, South Beirut as perceived by Syrian refugees. A lack of safety and security coupled with economic hardship rendered refugees even more susceptible to exploitation and harassment. Parental violence was the most commonly reported type of domestic violence.
Inhibiting PAD2 enhances the anti-tumor effect of docetaxel in tamoxifen-resistant breast cancer cells
Authors: Li Fujun , Miao Lixia , Xue Teng , Qin Hao , Mondal Santanu , Thompson Paul R. , Coonrod Scott A. , Liu Xiaoqiu , Zhang Xuesen
Published: October 2019

Background

Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms of tamoxifen resistance can guide development of efficient therapies to prevent drug resistance.

Methods

We first tested whether peptidylarginine deiminase 2 (PAD2) may be involved in tamoxifen-resistance in breast cancer cells. The effect of depleting or inhibiting PAD2 in tamoxifen-resistant MCF-7 (MCF7/TamR) cells was evaluated both in vitro and in vivo. We then investigated the potential of Cl-amidine, a PAD inhibitor, to be used in combination with tamoxifen or docetaxel, and further explored the mechanism of the synergistic and effective drug regimen of PADs inhibitor and docetaxel on tamoxifen-resistant breast cancer cells.

Results

We report that PAD2 is dramatically upregulated in tamoxifen-resistant breast cancer. Depletion of PAD2 in MCF7/TamR cells facilitated the sensitivity of MCF7/TamR cells to tamoxifen. Moreover, miRNA-125b-5p negatively regulated PAD2 expression in MCF7/TamR cells, therefore overexpression of miR-125b-5p also increased the cell sensitivity to tamoxifen. Furthermore, inhibiting PAD2 with Cl-amidine not only partially restored the sensitivity of MCF7/TamR cells to tamoxifen, but also more efficiently enhanced the efficacy of docetaxel on MCF7/TamR cells with lower doses of Cl-amidine and docetaxel both in vivo and in vivo. We then showed that combination treatment with Cl-amidine and docetaxel enhanced p53 nuclear accumulation, which synergistically induced cell cycle arrest and apoptosis. Meanwhile, p53 activation in the combination treatment also accelerated autophagy processes by synergistically decreasing the activation of Akt/mTOR signaling, thus enhancing the inhibition of proliferation.

Conclusion

Our results suggest that PAD2 functions as an important new biomarker for tamoxifen-resistant breast cancers and that inhibiting PAD2 combined with docetaxel may offer a new approach to treatment of tamoxifen-resistant breast cancers.
Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients
Authors: Peters Brandilyn A. , Wilson Melissa , Moran Una , Pavlick Anna , Izsak Allison , Wechter Todd , Weber Jeffrey S. , Osman Iman , Ahn Jiyoung
Published: October 2019

Background

Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community.

Methods

In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression.

Results

Higher microbial community richness was associated with longer PFS in 16S and shotgun data (p < 0.05). Clustering based on overall microbiome composition divided patients into three groups with differing PFS; the low-risk group had 99% lower risk of progression than the high-risk group at any time during follow-up (p = 0.002). Among the species selected in regression, abundance ofBacteroides ovatus,Bacteroides dorei,Bacteroides massiliensis,Ruminococcus gnavus, andBlautia productawere related to shorter PFS, andFaecalibacterium prausnitzii,Coprococcus eutactus,Prevotella stercorea,Streptococcus sanguinis,Streptococcus anginosus, andLachnospiraceae bacterium 3 1 46FAAto longer PFS. Metagenomic functions related to PFS that had correlated metatranscriptomic expression included risk-associated pathways ofl-rhamnose degradation, guanosine nucleotide biosynthesis, and B vitamin biosynthesis.

Conclusions

This work adds to the growing evidence that gut microbiota are related to immunotherapy outcomes, and identifies, for the first time, transcriptionally expressed metagenomic pathways related to PFS. Further research is warranted on microbial therapeutic targets to improve immunotherapy outcomes.
DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer
Authors: Awada Z. , Nasr R. , Akika R. , Cahais V. , Cuenin C. , Zhivagui M. , Herceg Z. , Ghantous A. , Zgheib N. K.
Published: October 2019

Background

Bisphenol A (BPA), an estrogen-like endocrine disruptor used in plastics, has been associated with development and promotion of breast cancer, so plastic manufacturers shifted towards less-studied analogs, BPF and BPS. Studying the associated DNA methylome-wide mechanisms of these derivatives is timely, particularly in comparison with BPA.

Methods

We assessed proliferation, cell cycle, and migration of breast cancer cells (estrogen receptor (ER)-positive: MCF-7 and ER-negative: MDA-MB-231) treated with BPF and BPS ± estrogen receptor inhibitor (ERI) in comparison to BPA ± ERI. RNA expression and activity of DNA (de)methylation enzymes andLINE-1methylation were quantified. DNA methylome-wide analysis was evaluated in bisphenol-exposed cells and compared to clinical breast cancer data.

Results

The three bisphenols caused ER-dependent increased proliferation and migration of MCF-7 but not MDA-MB-231 cells, with BPS being 10 times less potent than BPA and BPF. Although they have similar chemical structures, the three bisphenols induced differential DNA methylation alterations at several genomic clusters of or single CpG sites, with the majority of these being ER-dependent. At equipotent doses, BPA had the strongest effect on the methylome, followed by BPS then BPF. No pathways were enriched for BPF while BPA- and BPS-induced methylome alterations were enriched in focal adhesion, cGMP-PKG, and cancer pathways, which were also dysregulated in methylome-wide alterations comparing ER-positive breast cancer samples to adjacent normal tissues.

Conclusions

The three bisphenols have important epigenetic effects in breast cell lines, with those of BPA and BPS overlapping with cancer-related pathways in clinical breast cancer models. Hence, further investigation of their safety is warranted.
Oscillation of third-order neutral differential equations with damping and distributed delay
Authors: Wei Meihua , Jiang Cuimei , Li Tongxing
Published: October 2019

The present paper focuses on the oscillation of the third-order nonlinear neutral differential equations with damping and distributed delay. The oscillation of the third-order damped equations is often discussed by reducing the equations to the second-order ones. However, by applying the Riccati transformation and the integral averaging technique, we give an analytical method for the estimation of Riccati dynamic inequality to establish several oscillation criteria for the discussed equation, which show that any solution either oscillates or converges to zero. The results make significant improvement and extend the earlier works such as (Zhang et al. in Appl. Math. Lett. 25:1514–1519 2012). Finally, some examples are given to demonstrate the effectiveness of the obtained oscillation results.