bluuebunny/crossref_metadata_2025_split huggingface dataset:
PSEN1-selective gamma-secretase inhibition in combination with kinase or XPO-1 inhibitors effectively targets T cell acute lymphoblastic leukemia
Authors: Govaerts Inge , Prieto Cristina , Vandersmissen Charlien , Gielen Olga , Jacobs Kris , Provost Sarah , Nittner David , Maertens Johan , Boeckx Nancy , De Keersmaecker Kim , Segers Heidi , Cools Jan 
Published: June 2021

AbstractBackgroundT cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype that comprises 10–15% of childhood and 20–25% of adult ALL cases. Over 70% of T-ALL patients harbor activating mutations in the NOTCH1 signaling pathway and are predicted to be sensitive to gamma-secretase inhibitors. We have recently demonstrated that selective inhibition of PSEN1-containing gamma-secretase complexes can overcome the dose-limiting toxicity associated with broad gamma-secretase inhibitors. In this study, we developed combination treatment strategies with the PSEN1-selective gamma-secretase inhibitor MRK-560 and other targeted agents (kinase inhibitors ruxolitinib and imatinib; XPO-1 inhibitor KPT-8602/eltanexor) for the treatment of T-ALL.MethodsWe treated T-ALL cell lines in vitro and T-ALL patient-derived xenograft (PDX) models in vivo with MRK-560 alone or in combination with other targeted inhibitors (ruxolitinib, imatinib or KPT-8602/eltanexor). We determined effects on proliferation of the cell lines and leukemia development and survival in the PDX models.ResultsAll NOTCH1-signaling-dependent T-ALL cell lines were sensitive to MRK-560 and its combination with ruxolitinib or imatinib in JAK1- or ABL1-dependent cell lines synergistically inhibited leukemia proliferation. We also observed strong synergy between MRK-560 and KPT-8602 (eltanexor) in all NOTCH1-dependent T-ALL cell lines. Such synergy was also observed in vivo in a variety of T-ALL PDX models with NOTCH1 or FBXW7 mutations. Combination treatment significantly reduced leukemic infiltration in vivo and resulted in a survival benefit when compared to single treatment groups.We did not observe weight loss or goblet cell hyperplasia in single drug or combination treated mice when compared to control.ConclusionsThese data demonstrate that the antileukemic effect of PSEN1-selective gamma-secretase inhibition can be synergistically enhanced by the addition of other targeted inhibitors. The combination of MRK-560 with KPT-8602 is a highly effective treatment combination, which circumvents the need for the identification of additional mutations and provides a clear survival benefit in vivo. These promising preclinical data warrant further development of combination treatment strategies for T-ALL based on PSEN1-selective gamma-secretase inhibition.
HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML
Authors: Li Zheng , Wang Fangce , Tian Xiaoxue , Long Jun , Ling Bin , Zhang Wenjun , Xu Jun , Liang Aibin 
Published: June 2021

Abstract
Background:
Leukaemia stem cells (LSCs) are responsible for the initiation, maintenance, and recurrence of acute myeloid leukaemia (AML), an aggressive haematological malignancy associated with drug resistance and relapse. Identifying therapeutic LSC targets is critical to curing AML.

Methods
Bioinformatics databases were used to identify therapeutic LSC targets. The conditional knockout mice were used to analyse the role of HCK in leukaemogenesis or normal haematopoiesis. Colony-forming assays, cell counting, and flow cytometry were used to detect the viability and function of leukaemia cells. RT-PCR, western blotting, and RNA sequencing were used to detect mRNA and protein expression.

Result
HCK is expressed at higher levels in LSCs than in haematopoietic stem cells (HSCs), and high HCK levels are correlated with reduced survival time in AML patients. Knockdown of HCK leads to cell cycle arrest, which results in a dramatic decrease in the proliferation and colony formation in human AML cell lines. Moreover, HCK is required for leukemogenesis and leukaemia maintenance in vivo and in vitro. HCK is necessary for the self-renewal of LSCs during serial transplantation and limiting dilution assay. The phenotypes resulting from HCK deficiency can be rescued by CDK6 overexpression in the human cell line. RNA sequencing and gene expression have demonstrated that HCK may sustain cell cycle entry and maintain the self-renewal ability of LSCs through activating the ERK1/2-c-Myc-CDK6 signalling axis. In contrast, HCK deletion does not affect normal haematopoiesis or haematopoietic reconstruction in mice.

Conclusions
HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML and may be an ideal therapeutic target for eradicating LSCs without influencing normal haematopoiesis.
Pediatric interregional healthcare mobility in Italy
Authors: De Curtis Mario , Bortolan Francesco , Diliberto Davide , Villani Leonardo 
Published: June 2021

Abstract
Background
The analysis of interregional healthcare mobility represents one of the main criteria for evaluating Regional Healthcare Systems, both in terms of its economic-financial relevance and the quality and satisfaction of the services provided. The aim of the study is to analyze healthcare mobility and its associated cost in Italy in 2019 for all children ≤ 14 years of age.

Methods
We collected data from the “Rapporto annuale sull’attività di ricovero ospedaliero – Dati SDO 2019” published by the Italian Ministry of Health. These data represent the tool for collecting information relating to all hospitalization services provided in accredited public and private hospitals present throughout the national territory. We collected data for all Italian regions and clustered them in two geographical areas: Center-North regions and South regions (including Sicily and Sardinia). We have analyzed the magnitude of the mobility of children among regions and in particular from the South to the Center-North and the relative cost of this interregional mobility.

Results
The hospitalization rate of children residing in the South regions was higher than that of children residing in the Center-North regions (13.9% vs 12.3%). Children residing in the South were more frequently treated in other regions than those living in the Center-North (11.9% vs 6.9%). Even considering the high complexity hospitalizations, children living in the South more frequently underwent treatment in other regions (21.3% vs 10.5% of the Center-North). The cost of passive mobility amounts to € 103.9 million for the South regions (15.1% of the total hospitalizations’ expenditure) and the 87.1% of this cost refers to the mobility to the hospitals of Center-North. The cost of healthcare migration from South regions to other South regions was much lower (12.9%, equal to € 13.4 million).

Conclusions
Healthcare mobility, while affecting all Italian regions, is particularly relevant in the South regions and indicates a lack of pediatric care, which should be strengthened by creating services that are currently not evenly distributed throughout the territory.
Optimizing expression quantitative trait locus mapping workflows for single-cell studies
Authors: Cuomo Anna S. E. , Alvari Giordano , Azodi Christina B. ,   single-cell eQTLGen consortium, McCarthy Davis J. , Bonder Marc Jan 
Published: June 2021

AbstractBackgroundSingle-cell RNA sequencing (scRNA-seq) has enabled the unbiased, high-throughput quantification of gene expression specific to cell types and states. With the cost of scRNA-seq decreasing and techniques for sample multiplexing improving, population-scale scRNA-seq, and thus single-cell expression quantitative trait locus (sc-eQTL) mapping, is increasingly feasible. Mapping of sc-eQTL provides additional resolution to study the regulatory role of common genetic variants on gene expression across a plethora of cell types and states and promises to improve our understanding of genetic regulation across tissues in both health and disease.ResultsWhile previously established methods for bulk eQTL mapping can, in principle, be applied to sc-eQTL mapping, there are a number of open questions about how best to process scRNA-seq data and adapt bulk methods to optimize sc-eQTL mapping. Here, we evaluate the role of different normalization and aggregation strategies, covariate adjustment techniques, and multiple testing correction methods to establish best practice guidelines. We use both real and simulated datasets across single-cell technologies to systematically assess the impact of these different statistical approaches.ConclusionWe provide recommendations for future single-cell eQTL studies that can yield up to twice as many eQTL discoveries as default approaches ported from bulk studies.
Characterization of the gut microbiota in diabetes mellitus II patients with adequate and inadequate metabolic control
Authors: Hamasaki-Matos Angie Joyce , Cóndor-Marín Katherine Marlene , Aquino-Ortega Ronald , Carrillo-Ng Hugo , Ugarte-Gil Cesar , Silva-Caso Wilmer , Aguilar-Luis Miguel Angel , del Valle-Mendoza Juana 
Published: June 2021

Abstract
Objective
The objective of this study was to characterize the composition of the gut microbiota in type 2 Diabetes Mellitus (T2DM) patients with adequate and inadequate metabolic control, and its relationship with fiber consumption.

Results
A total of 26 patients with type 2 diabetes mellitus (T2DM) were enrolled, of which 7 (26.9%) cases had adequate metabolic control (HbA1c < 7%) and 19 (73.1%) inadequate metabolic control (HbA1c ≥ 7%). It was observed that among patients with controlled T2DM, 2 (28.6%) cases presented good intake of fiber and 5 (71.4%) cases a regular intake. In contrast, in patients with uncontrolled T2DM, 13 (68.4%) patients reported a regular intake and 6 (31.6%) a poor intake. In relation to the identification of the gut microbiota, both groups presented a similar characterization. There were differences in the population of bacteria identified in both groups, however, the results were not statistically significant. The most frequently identified bacteria in controlled and uncontrolled T2DM patients were Prevotella (71.4% vs 52.6%), followed by Firmicutes (71.4% vs 42.1%), Proteobacteria (71.4% vs 36.8%) and Bacteroidetes (57.1% vs 37.8%). On the other hand, Fusobacterium, Actinobacteria were not identified in either of the two groups of study.
Analysis on risk factors for neck shortening after internal fixation for Pauwels II femoral neck fracture in young patients
Authors: Zhao Fulong , Guo Lijuan , Wang Xuefei , Zhang Yakui 
Published: June 2021

AbstractBackgroundFemoral neck shortening can occur in young patients receiving internal fixation for Pauwels type II femoral neck fracture. The risk factors for neck shortening, which can affect hip function, are not clear. This study aimed to retrospectively identify risk factors for neck shortening after internal fixation with parallel partially threaded cannulated cancellous screws (FPTCS) for Pauwels type II femoral neck fracture in relatively young patients.MethodsClinical data from 122 cases with Pauwels type II femoral neck fracture from February 2014 to February 2019 were reviewed and analyzed, and causes of neck shortening were statistically analyzed. And the Chi-squared test or Fisher’s exact test was used to compare indicators. Multivariate analysis was conducted with non-conditional logistic regression analysis.ResultsStatistically significant differences were found in age, sex, BMD, BMI, fracture type, posterior medial cortex comminution, and reduction quality between patients with femoral neck shortening and those without femoral neck shortening. Logistic regression analysis showed that fracture type, posterior medial cortex comminution, and reduction quality were the main risk factors for neck shortening.ConclusionFracture type, posterior medial cortex comminution, and reduction quality can be used as important reference indexes to predict the possibility of neck shortening after internal fixation with FPTCS for Pauwels type II femoral neck fracture in young patients. BMD and BMI may be also risk factors.
The prevalence of Listeria species in different food items of animal and plant origin in Ethiopia: a systematic review and meta-analysis
Authors: Diriba Kuma , Awulachew Ephrem , Diribsa Kuma 
Published: June 2021

Abstract
Background
Listeriosis is one of the important emerging zoonotic disease affecting human health following the consumption of contaminated food of animal origin. It results in serious clinical complications in humans with a high case facility rate. Therefore, this systematic review and meta-analysis aimed to estimate the pooled prevalence of Listeria species in Ethiopia.

Methods
A systematic search was conducted on PubMed, Web of Science, EMBASE, Google Scholar and the Cochrane Library. All identified observational studies reporting the prevalence of Listeria species in different food items of animal and plant origin in Ethiopia were included. Three authors independently extracted data and analyzed them using STATA Version 13 statistical software. A random effects model was computed to estimate the pooled prevalence of Listeria species in Ethiopia.

Results
After reviewing 122 studies, five studies fulfilled the inclusion criteria were included in the meta-analysis. The findings from the five studies revealed that the pooled prevalence of Listeria species in different food items of animal and plant origin in Ethiopia was 27% (95% CI 25, 29). The highest prevalence of Listeria species was reported in beef meat followed by ice cream with prevalence rates of 62% (95% CI 50, 75) and 43% (95% CI 33, 53), respectively.

Conclusion
The presence of Listeria species in different food items of animal and plant origin in Ethiopia is an indicator of the presence of public health hazards to the consumer, particularly to the high-risk groups. Hence, awareness creation on food safety and implementation of regulations is strongly recommended.
Duration of hospital admission in severe mental illness: is longer better?
Authors: Ismail Haitham 
Published: June 2021

SUMMARYA Cochrane review has compared short-stay hospital admission with long-stay/standard admission of patients with severe mental illness for a number of outcomes in a total 2030 participants from 6 randomised trials. It reached the conclusion, supported by limited evidence, that short admissions in mental health units do not increase the risk of death, readmission or worsening of mental state, and pose less risk of delayed discharge and patient's unemployment. This commentary examines the available evidence from previous studies and discusses its relevance to current practice.
Investigating associations of childhood abuse and serum brain-derived neurotrophic factor levels with suicidal behaviours in patients with depressive disorders
Authors: Kim Jae-Min , Kim Ju-Wan , Kang Hee-Ju , Lee Ju-Yeon , Kim Sung-Wan , Shin Il-Seon , Chun Byung-Jo , Stewart Robert 
Published: June 2021

BackgroundThe role of childhood abuse and serum brain-derived neurotrophic factor (BDNF) levels in suicidal behaviour is controversial.AimsWe aimed to investigate the individual and interactive effects of the childhood abuse and serum BDNF on suicidal behaviour before and after pharmacologic treatment in patients with depressive disorders.MethodAt baseline, reported childhood emotional, physical and sexual abuse were ascertained and serum BDNF levels were measured in 1094 patients with depressive disorder, 884 of whom were followed during a 1-year period of stepwise pharmacotherapy. Suicidal behaviours evaluated at baseline were previous suicide attempt and baseline suicide severity, and suicidal behaviours evaluated at follow-up were increased suicide severity and fatal/non-fatal suicide attempt. Individual and interactive associations of any childhood abuse and serum BDNF levels with four types of suicidal behaviours were analysed using logistic regression models, after adjusting relevant covariates.ResultsIndividual associations of childhood abuse were significant only with previous suicide attempt, and no significant individual associations were found for serum BDNF with any suicide outcome. However, the presence of both childhood abuse and lower serum BDNF levels was associated with the highest prevalence/incidence of all four suicidal behaviours, with significant interactions for baseline suicide severity and fatal/non-fatal suicide attempt during follow-up.ConclusionsSynergistic interactive effects of child abuse and serum BDNF levels on suicidal behaviours were found before and after pharmacologic treatment in patients with depressive disorders. Information combining childhood abuse and serum BDNF levels could improve predictions of suicidal behaviour in patients with depressive disorders.
Comprehensive Breast Cancer Risk Assessment for CHEK2 and ATM Pathogenic Variant Carriers Incorporating a Polygenic Risk Score and the Tyrer-Cuzick Model
Authors: Gallagher Shannon , Hughes Elisha , Kurian Allison W. , Domchek Susan M. , Garber Judy , Probst Braden , Morris Brian , Tshiaba Placede , Meek Stephanie , Rosenthal Eric , Roa Benjamin , Slavin Thomas P. , Wagner Susanne , Weitzel Jeffrey , Gutin Alexander , Lanchbury Jerry S. , Robson Mark 
Published: June 2021

PURPOSE Breast cancer risks for CHEK2 and ATM pathogenic variant (PV) carriers are modified by an 86-single nucleotide polymorphism polygenic risk score (PRS) and individual clinical factors. Here, we describe comprehensive risk prediction models for women of European ancestry combining PV status, PRS, and individual clinical variables. MATERIALS AND METHODS This study included deidentified clinical records from 358,095 women of European ancestry who received testing with a multigene panel (September 2013 to November 2019). Model development included CHEK2 PV carriers (n = 4,286), ATM PV carriers (n = 2,666), and women negative for other breast cancer risk gene PVs (n = 351,143). Odds ratios (ORs) were calculated using multivariable logistic regression with adjustment for familial cancer history. Risk estimates incorporating PV status, PRS, and Tyrer-Cuzick v7.02 were calculated using a Fixed-Stratified method that accounts for correlations between risk factors. Stratification of PV carriers into risk categories on the basis of remaining lifetime risk (RLR) was assessed in independent cohorts of PV carriers. RESULTS ORs for association of PV status with breast cancer were 2.01 (95% CI, 1.88 to 2.16) and 1.83 (95% CI, 1.68 to 2.00) for CHEK2 and ATM PV carriers, respectively. ORs for PRS per one standard deviation were 1.51 (95% CI, 1.37 to 1.66) and 1.45 (95% CI, 1.30 to 1.64) in CHEK2 and ATM PV carriers, respectively. Using the combined model (PRS plus Tyrer-Cuzick plus PV status), RLR was low (≤ 20%) for 24.2% of CHEK2 PV carriers, medium (20%-50%) for 63.8%, and high (> 50%) for 12.0%. Among ATM PV carriers, RLR was low for 31.5% of patients, medium for 58.5%, and high for 9.7%. CONCLUSION In CHEK2 and ATM PV carriers, risk assessment including PRS, Tyrer-Cuzick, and PV status has the potential for more precise direction of screening and prevention strategies.
The Feminization of Translation
Authors: Godley Min Young 
Published: June 2021

Abstract
The awarding of the 2016 Man Booker International Prize to Deborah Smith’s English translation of The Vegetarian brought global recognition to emergent Korean literature, but domestically it has sparked outrage among numerous Korean scholars who believe the literal inaccuracies in Smith’s translation have brought about a “national disgrace.” Situating this overheated reaction in the larger context of the colonial history of Korean nationalism, this article points out the irony that the “noble cause” of anti-imperialist resistance has historically led to the silencing of women’s voices in the context of preserving and transmitting an idea of quintessential Korean culture to an international audience. Such nationalist tendencies demand the “feminization” of the translator—requesting her to be barely visible while performing a self-effacing humility in deference to the putatively “original” culture. In contrast to this tendency, reading Han’s original and Smith’s translation together makes visible the damages that both colonization and nationalism have inflicted on the representation of female experiences. In the end, what truly scandalizes nationalist critics is not the failure of the translator to accurately convey Korean experiences, but the success of the translation in conveying an area of Korean experience they tend to neglect: that of female subjectivity.
me31B regulates stem cell homeostasis by preventing excess dedifferentiation in the Drosophila male germline
Authors: Jensen Lindy , Venkei Zsolt G. , Watase George J. , Bisai Bitarka , Pletcher Scott , Lee Cheng-Yu , Yamashita Yukiko M. 
Published: June 2021

ABSTRACT
Tissue-specific stem cells maintain tissue homeostasis by providing a continuous supply of differentiated cells throughout the life of organisms. Differentiated/differentiating cells can revert back to a stem cell identity via dedifferentiation to help maintain the stem cell pool beyond the lifetime of individual stem cells. Although dedifferentiation is important for maintaining the stem cell population, it is speculated that it underlies tumorigenesis. Therefore, this process must be tightly controlled. Here, we show that a translational regulator, me31B, plays a critical role in preventing excess dedifferentiation in the Drosophila male germline: in the absence of me31B, spermatogonia dedifferentiate into germline stem cells (GSCs) at a dramatically elevated frequency. Our results show that the excess dedifferentiation is likely due to misregulation of nos, a key regulator of germ cell identity and GSC maintenance. Taken together, our data reveal negative regulation of dedifferentiation to balance stem cell maintenance with differentiation.
More is More? Total Pancreatectomy for Periampullary Cancer as an Alternative in Patients with High-Risk Pancreatic Anastomosis: A Propensity Score-Matched Analysis
Authors: Hempel Sebastian , Oehme Florian , Tahirukaj Ermal , Kolbinger Fiona R. , Müssle Benjamin , Welsch Thilo , Weitz Jürgen , Distler Marius 
Published: June 2021

Abstract
Background
Postpancreatectomy morbidity remains significant even in high-volume centers and frequently results in delay or suspension of indicated adjuvant oncological treatment. This study investigated the short-term and long-term outcome after primary total pancreatectomy (PTP) and pylorus-preserving pancreaticoduodenectomy (PPPD) or Whipple procedure, with a special focus on administration of adjuvant therapy and oncological survival.

Methods
Patients who underwent PTP or PPPD/Whipple for periampullary cancer between January 2008 and December 2017 were retrospectively analyzed. Propensity score-matched analysis was performed to compare perioperative and oncological outcomes. Correspondingly, cases of rescue completion pancreatectomy (RCP) were analyzed.

Results
In total, 41 PTP and 343 PPPD/Whipple procedures were performed for periampullary cancer. After propensity score matching, morbidity (Clavien-Dindo classification (CDC) ≥ IIIa, 31.7% vs. 24.4%; p = 0.62) and mortality rates (7.3% vs. 2.4%, p = 0.36) were similar in PTP and PPPD/Whipple. Frequency of adjuvant treatment administration (76.5% vs. 78.4%; p = 0.87), overall survival (513 vs. 652 days; p = 0.47), and progression-free survival (456 vs. 454 days; p = 0.95) did not significantly differ. In turn, after RCP, morbidity (CDC ≥ IIIa, 85%) and mortality (40%) were high, and overall survival was poor (median 104 days). Indicated adjuvant therapy was not administered in 77%.

Conclusions
In periampullary cancers, PTP may provide surgical and oncological treatment outcomes comparable with pancreatic head resections and might save patients from RCP. Especially in selected cases with high-risk pancreatic anastomosis or preoperatively impaired glucose tolerance, PTP may provide a safe treatment alternative to pancreatic head resection.