bluuebunny/crossref_metadata_2025_split huggingface dataset:
KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas
Authors: Heward James , Koniali Lola , D’Avola Annalisa , Close Karina , Yeomans Alison , Philpott Martin , Dunford James , Rahim Tahrima , Al Seraihi Ahad F. , Wang Jun , Korfi Koorosh , Araf Shamzah , Iqbal Sameena , Bewicke-Copley Findlay , Kumar Emil , Barisic Darko , Calaminici Maria , Clear Andrew , Gribben John , Johnson Peter , Neve Richard , Cutillas Pedro , Okosun Jessica , Oppermann Udo , Melnick Ari , Packham Graham , Fitzgibbon Jude 
Published: March 2021

Abstract
Loss-of-function mutations in KMT2D are a striking feature of germinal center (GC) lymphomas, resulting in decreased histone 3 lysine 4 (H3K4) methylation and altered gene expression. We hypothesized that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would reestablish H3K4 methylation and restore the expression of genes repressed on loss of KMT2D. KDM5 inhibition increased H3K4me3 levels and caused an antiproliferative response in vitro, which was markedly greater in both endogenous and gene-edited KMT2D mutant diffuse large B-cell lymphoma cell lines, whereas tumor growth was inhibited in KMT2D mutant xenografts in vivo. KDM5 inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signaling and altered expression of B-cell lymphoma 2 (BCL2) family members, including BCL2 itself. KDM5 inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC lymphomas.
Synergistic efficacy of the dual PI3K-δ/γ inhibitor duvelisib with the Bcl-2 inhibitor venetoclax in Richter syndrome PDX models
Authors: Iannello Andrea , Vitale Nicoletta , Coma Silvia , Arruga Francesca , Chadburn Amy , Di Napoli Arianna , Laudanna Carlo , Allan John N. , Furman Richard R. , Pachter Jonathan A. , Deaglio Silvia , Vaisitti Tiziana 
Published: March 2021

AbstractA small subset of cases of chronic lymphocytic leukemia undergoes transformation to diffuse large B-cell lymphoma, Richter syndrome (RS), which is associated with a poor prognosis. Conventional chemotherapy results in limited responses, underlining the need for novel therapeutic strategies. Here, we investigate the ex vivo and in vivo efficacy of the dual phosphatidylinositol 3-kinase-δ/γ (PI3K-δ/γ) inhibitor duvelisib (Duv) and the Bcl-2 inhibitor venetoclax (Ven) using 4 different RS patient-derived xenograft (PDX) models. Ex vivo exposure of RS cells to Duv, Ven, or their combination results in variable apoptotic responses, in line with the expression levels of target proteins. Although RS1316, IP867/17, and RS9737 cells express PI3K-δ, PI3K-γ, and Bcl-2 and respond to the drugs, RS1050 cells, expressing very low levels of PI3K-γ and lacking Bcl-2, are fully resistant. Moreover, the combination of these drugs is more effective than each agent alone. When tested in vivo, RS1316 and IP867/17 show the best tumor growth inhibition responses, with the Duv/Ven combination leading to complete remission at the end of treatment. The synergistic effect of Duv and Ven relies on the crosstalk between PI3K and apoptotic pathways occurring at the GSK3β level. Indeed, inhibition of PI3K signaling by Duv results in GSK3β activation, leading to ubiquitination and subsequent degradation of both c-Myc and Mcl-1, making RS cells more sensitive to Bcl-2 inhibition by Ven. This work provides, for the first time, a proof of concept of the efficacy of dual targeting of PI3K-δ/γ and Bcl-2 in RS and providing an opening for a Duv/Ven combination for these patients. Clinical studies in aggressive lymphomas, including RS, are under way. This trial was registered at www.clinicaltrials.gov as #NCT03892044.
Oscillatory shear stress promotes angiogenic effects in arteriovenous malformations endothelial cells
Authors: Ryu Jeong Yeop , Kim Yun Hyun , Lee Joon Seok , Lee Jeong Woo , Oh Eun Jung , Kim Hyun Mi , Lee Seok-Jong , Lee Jongmin , Lee Sang Yub , Huh Seung , Kim Ji Yoon , Im Saewon , Chung Ho Yun 
Published: March 2021

Abstract
Background
Vascular endothelial cells (ECs) are subject to continuous shear stress due to blood circulation. Mechanical stress due to high shear flow can also cause arteriovenous malformation (AVM) when ECs respond hyper-sensitively to shear flow. This study was conducted to test the hypothesis that angiogenesis could be promoted in response to mechanical stress via regulation of pro-angiogenic factors in AVM cells.

Methods
ECs were extracted from the tissue samples from six AVM patients and six normal patients. Shear stress at 7 dynes/cm2 were applied for 24 h. Before and after application of shear stress to each group, RT-PCR was performed to access the expression levels of angiopoietin2(AGP2), aquaporin1(AQP1) and TGFβR1. Immunofluorescences was also performed to evaluate the level of protein expressions.

Results
In both normal and AVM tissues, AGP2 and TGFβR1 under the shear stress showed increased expression in the ECs compared to the non-sheared samples. When AVMs and normal arterial vasculature were compared, the expression levels of both AGP2 and TGFβR1 in AVMs were higher when compared to normal arterial vasculature with or without shear stress. Immunofluorescence-based protein analysis also confirmed shear-induced AGP2 and TGFβR1 in both samples of normal and AVM patients.

Conclusions
AVMs exhibited higher sensitivity to shear stress by producing higher expressions of some marked genes and proteins that regulate the endothelial functions upon exposure to shear stress. While the physiological mechanism for AVMs remain elusive, our study shows the plausibility of physical stress imposed by the shearing flow can cause the occurrence of AVMs.
Non-lead rifle ammunition: Danish hunters’ attitudes
Authors: Kanstrup Niels , Balsby Thorsten Johannes Skovbjerg , Mellerup Kavi Askholm , Hansen Hans Peter 
Published: March 2021

Abstract
Background
Lead particles from hunting rifle ammunition become embedded in the tissue of shot animals and pose a health risk to predators and scavengers that eat discarded offal or parts of non-retrieved carcasses of shot game animals, as well as to humans who consume game. Copper and copper–zinc alloys are the most widely used alternatives to leaded ammunition. In Denmark, there has been a growing awareness of the toxic environmental effects of lead ammunition and the Danish government, supported by the Danish Hunters’ Association, announced in November 2020 a forthcoming ban on the use of lead-based bullets for hunting purposes intended to take effect in 2023. The question that remains to be addressed is how the Danish hunting community perceives lead ammunition as a problem and non-lead alternatives as a solution, and whether the willingness to change demonstrated by the hunters’ representatives reflects the attitude of the individual hunters. We studied this in a survey targeting 6000 randomly selected Danish rifle hunters, mapping their knowledge and concerns regarding lead rifle ammunition as well as their use of lead and non-lead ammunition.

Results
We found that approximately one-fifth of the use of rifle ammunition for hunting in Denmark in 2019 was non-lead. Hunters’ knowledge of and concern for the adverse impacts of lead ammunition and the opportunities to switch to non-lead alternatives were generally limited. However, some showed an open-minded attitude and we found that such knowledge and concern increased the likelihood of hunters deciding to use non-lead ammunition. Hunters mainly got their information from hunting organizations and colleagues and expressed a distinct lack of information and guidance on the topic from ministerial authorities responsible for hunting administration.

Conclusions
Some hunters have already changed to use non-lead rifle ammunition completely or in part, and others show an open attitude to discussing the issue and receiving more information particularly from hunting authorities. Some hunters demonstrated a critical or negative attitude towards a change. Communication of the adverse impacts of leaded ammunition in terms of the risk of lead poisoning to wildlife and humans and the opportunities of switching to the existing efficient and safe alternatives is essential regardless of the formal approach and will be crucial for the effectiveness of the regulation announced by the Danish government.
Evaluating ecological risks and tracking potential factors influencing heavy metals in sediments in an urban river
Authors: Liu Dongping , Wang Jian , Yu Huibin , Gao Hongjie , Xu Weining 
Published: March 2021

Abstract
Background
Heavy metal pollution of aquatic systems is a global issue that has received considerable attention. Canonical correlation analysis (CCA), principal component analysis (PCA), and potential ecological risk index (PERI) have been applied to heavy metal data to trace potential factors, identify regional differences, and evaluate ecological risks. Sediment cores of 200 cm in depth were taken using a drilling platform at 10 sampling sites along the Xihe River, an urban river located in western Shenyang City, China. Then they were divided into 10 layers (20 cm each layer). The concentrations of the As, Cd, Cr, Cu, Hg, Ni, Pb and Zn were measured for each layer. Eight heavy metals, namely Pb, Zn, As, Cd, Cr, Cu, Ni, and Hg, were measured for each layer in this study.

Results
The average concentrations of the As, Cd, Cu, Hg, and Zn were significantly higher than their background values in soils in the region, and mainly gathered at 0–120 cm in depth in the upstream, 0–60 cm in the midstream, and 0–20 cm downstream. This indicated that these heavy metals were derived from the upstream areas where a large quantity of effluents from the wastewater treatment plants enter the river. Ni, Pb, and Cr were close or slightly higher than their background values. The decreasing order of the average concentration of Cd was upstream > midstream > downstream, so were Cr, Cu, Ni and Zn. The highest concentration of As was midstream, followed by upstream and then downstream, which was different to Cd. The potential factors of heavy metal pollution were Cd, Cu, Hg, Zn, and As, especially Cd and Hg with the high ecological risks. The ecological risk levels of all heavy metals were much higher in the upstream than the midstream and downstream.

Conclusions
Industrial discharge was the dominant source for eight heavy metals in the surveyed area, and rural domestic sewage has a stronger influence on the Hg pollution than industrial pollutants. These findings indicate that effective management strategies for sewage discharge should be developed to protect the environmental quality of urban rivers.
Is ferroptosis involved in ROS-induced testicular lesions in a varicocele rat model?
Authors: Shaygannia Erfaneh , Nasr-Esfahani Mohammad H. , Sotoodehnejadnematalahi Fattah , Parivar Kazem 
Published: March 2021

Abstract
Background
Ferroptosis is an iron-dependent cell death that is distinct from apoptosis. Based on excessive amounts of iron and reactive oxygen species in varicocele (VCL) rats, we hypothesize that ferroptosis might be involved in VCL. In addition, since alpha-lipoic acid (ALA) was shown to have both antioxidant and anti-ferroptotic activity we assessed in the present work the status of ferroptosis in our varicocele model and the protective effect of ALA. To this end, 70 male Wistar rats were divided into 7 groups: control, sham and varicocele groups which were initially sacrificed 2 months after the operation to verify the induction of varicocele. A second batch of the same 3 groups were sacrificed 4 months after varicocele induction to evaluate the effect of ALA supplementation. The parameters measured were chromatin integrity (aniline blue and acridine orange staining), lipid peroxidation (BODIPY staining), testicular morphometry and iron content. In addition, redox (GSH and NADPH) and ferroptosis (Nrf2, Slc7a11, P53 and p-Jnk) markers were evaluated at 2 and 4 months post-operation.

Result
The alteration of the spermatic parameters made it possible to verify the induction of the varicocele. Iron accumulated well in the testicles during varicocele and decreased significantly following ALA treatment. Ferroptotic molecular markers at the mRNA and protein levels were not significantly altered. ALA supplementation did not alter NADPH values, but increased GSH levels.

Conclusion
Despite the increased accumulation of iron in the testes 2 and 4 months after surgical induction of varicocele, molecular evidence did not demonstrate the involvement of ferroptosis. This could be explained by the mosaic nature of the varicocele affecting some seminiferous tubules and not others which could mask variations in molecular markers. In parallel, our study confirms that ALA stimulates the NRF2 pathway.
Reliable genomic strategies for species classification of plant genetic resources
Authors: van Bemmelen van der Plaat Artur , van Treuren Rob , van Hintum Theo J. L. 
Published: March 2021

Abstract
Background
To address the need for easy and reliable species classification in plant genetic resources collections, we assessed the potential of five classifiers (Random Forest, Neighbour-Joining, 1-Nearest Neighbour, a conservative variety of 3-Nearest Neighbours and Naive Bayes) We investigated the effects of the number of accessions per species and misclassification rate on classification success, and validated theirs generic value results with three complete datasets.

Results
We found the conservative variety of 3-Nearest Neighbours to be the most reliable classifier when varying species representation and misclassification rate. Through the analysis of the three complete datasets, this finding showed generic value. Additionally, we present various options for marker selection for classification taks such as these.

Conclusions
Large-scale genomic data are increasingly being produced for genetic resources collections. These data are useful to address species classification issues regarding crop wild relatives, and improve genebank documentation. Implementation of a classification method that can improve the quality of bad datasets without gold standard training data is considered an innovative and efficient method to improve gene bank documentation.
Six genes involved in prognosis of hepatocellular carcinoma identified by Cox hazard regression
Authors: Dai Qinghong , Liu Tao , Gao Yongchao , Zhou Honghao , Li Xiong , Zhang Wei 
Published: March 2021

Abstract
Background
Hepatocellular carcinoma (HCC), derived from hepatocytes, is the main histological subtype of primary liver cancer and poses a serious threat to human health due to the high incidence and poor prognosis. This study aimed to establish a multigene prognostic model to predict the prognosis of patients with HCC.

Results
Gene expression datasets (GSE121248, GSE40873, GSE62232) were used to identify differentially expressed genes (DEGs) between tumor and adjacent or normal tissues, and then hub genes were screened by protein–protein interaction (PPI) network and Cytoscape software. Seventeen genes among hub genes were significantly associated with prognosis and used to construct a prognostic model through COX hazard regression analysis. The predictive performance of this model was evaluated with TCGA data and was further validated with independent dataset GSE14520. Six genes (CDKN3, ZWINT, KIF20A, NUSAP1, HMMR, DLGAP5) were involved in the prognostic model, which separated HCC patients from TCGA dataset into high- and low-risk groups. Kaplan–Meier (KM) survival analysis and risk score analysis demonstrated that low-risk group represented a survival advantage. Univariate and multivariate regression analysis showed risk score could be an independent prognostic factor. The receiver operating characteristic (ROC) curve showed there was a better predictive power of the risk score than that of other clinical indicators. At last, the results from GSE14520 demonstrated the reliability of this prognostic model in some extent.

Conclusion
This prognostic model represented significance for prognosis of HCC, and the risk score according to this model may be a better prognostic factor than other traditional clinical indicators.
Diversity of short interspersed nuclear elements (SINEs) in lepidopteran insects and evidence of horizontal SINE transfer between baculovirus and lepidopteran hosts
Authors: Han Guangjie , Zhang Nan , Jiang Heng , Meng Xiangkun , Qian Kun , Zheng Yang , Xu Jian , Wang Jianjun 
Published: March 2021

Abstract
Background
Short interspersed nuclear elements (SINEs) belong to non-long terminal repeat (non-LTR) retrotransposons, which can mobilize dependent on the help of counterpart long interspersed nuclear elements (LINEs). Although 234 SINEs have been identified so far, only 23 are from insect species (SINEbase: http://sines.eimb.ru/).

Results
Here, five SINEs were identified from the genome of Plutella xylostella, among which PxSE1, PxSE2 and PxSE3 were tRNA-derived SINEs, PxSE4 and PxSE5 were 5S RNA-derived SINEs. A total of 18 related SINEs were further identified in 13 lepidopteran insects and a baculovirus. The 3′-tail of PxSE5 shares highly identity with that of LINE retrotransposon, PxLINE1. The analysis of relative age distribution profiles revealed that PxSE1 is a relatively young retrotransposon in the genome of P. xylostella and was generated by recent explosive amplification. Integration pattern analysis showed that SINEs in P. xylostella prefer to insert into or accumulate in introns and regions 5 kb downstream of genes. In particular, the PxSE1-like element, SlNPVSE1, in Spodoptera litura nucleopolyhedrovirus II genome is highly identical to SfSE1 in Spodoptera frugiperda, SlittSE1 in Spodoptera littoralis, and SlituSE1 in Spodoptera litura, suggesting the occurrence of horizontal transfer.

Conclusions
Lepidopteran insect genomes harbor a diversity of SINEs. The retrotransposition activity and copy number of these SINEs varies considerably between host lineages and SINE lineages. Host-parasite interactions facilitate the horizontal transfer of SINE between baculovirus and its lepidopteran hosts.
Use of therapeutic caffeine in acute care postoperative and critical care settings: a scoping review
Authors: Bright M. , Raman V. , Laupland K. B. 
Published: March 2021

Abstract
Background
Caffeine is the most utilised psychoactive drug worldwide. However, caffeine withdrawal and the therapeutic use of caffeine in intensive care and in the perioperative period have not been well summarised. Our objective was to conduct a scoping review of caffeine withdrawal and use in the intensive care unit (ICU) and postoperative patients.

Methods
PubMed, Embase, CINAHL Complete, Scopus and Web of Science were systematically searched for studies investigating the effects of caffeine withdrawal or administration in ICU patients and in the perioperative period. Areas of recent systematic review such as pain or post-dural puncture headache were not included in this review. Studies were limited to adults.

Results
Of 2268 articles screened, 26 were included and grouped into two themes of caffeine use in in the perioperative period and in the ICU. Caffeine withdrawal in the postoperative period increases the incidence of headache, which can be effectively treated prophylactically with perioperative caffeine. There were no studies investigating caffeine withdrawal or effect on sleep wake cycles, daytime somnolence, or delirium in the intensive care setting. Administration of caffeine results in faster emergence from sedation and anaesthesia, particularly in individuals who are at high risk of post-extubation complications. There has only been one study investigating caffeine administration to facilitate post-anaesthetic emergence in ICU. Caffeine administration appears to be safe in moderate doses in the perioperative period and in the intensive care setting.

Conclusions
Although caffeine is widely used, there is a paucity of studies investigating withdrawal or therapeutic effects in patients admitted to ICU and further novel studies are a priority.
A pilot study of 17 wrist-cutting suicide injuries in single institution: perspectives from a hand surgeon
Authors: Kim Jong-Ho , Yoo Hyokyung , Eun Seokchan 
Published: March 2021

Abstract
Background
Self-cutting is a special type of emergency in hand surgery. Despite its low mortality rate, it is clinically significant because there is a possibility of permanent disability and repeated suicide attempts are likely to occur. Therefore, we aim to understand the characteristics of self-inflicted wrist injuries and share the perspectives from a hand surgeon in order to inform those who face these patients primarily in the emergency room.

Methods
We reviewed 17 patients with self-inflicted wrist injuries who were referred to the Department of Hand surgery from the Emergency Medicine Department from 2013 to 2017. We investigated the differences in demographic features (age, gender, psychological diagnosis, alcohol consumption, prior suicide attempts) and clinical features (injury side, injury pattern, anatomical structures, distance from wrist crease).

Results
Among the patients, 4 were female and 13 were male. 70.6% of patients (12/17) had injuries on the left wrist and 94.1% of patients (16/17) had injuries on the flexor side. The average distance from the wrist crease to the injured site was 3.43 cm and 90.5% (19/21) of total injuries had an average distance of was less than 5 cm. The most frequently injured structures were palmaris longus tendon (58.5%, 10/17). 52.9% (9/17) of patients, among which 6 of the 8 patients with deep injuries and 3 of the 9 patients with superficial injuries, had a history of a psychiatric disorder.

Conclusions
We conclude that a male with a previously diagnosed psychiatric disorder has a higher chance of inflicting a deeper injury. In addition, self-cutting injuries are highly predictable because most of these injuries occur on the flexor side of the left wrist and are limited to a distance of 5 cm from the wrist crease. In terms of the implements used in self-inflicted injuries, we can predict the type of damage to some degree depending on the type of implement used. In view of these characteristics, more appropriate evaluation can be implemented in the emergency room and those who deal with these patients primarily can cope more effectively for better long-term results.