bluuebunny/crossref_metadata_2025_split huggingface dataset:
The polyphenol/saponin-rich Rhus tripartita extract has an apoptotic effect on THP-1 cells through the PI3K/AKT/mTOR signaling pathway
Authors: Tlili Hajer , Macovei Anca , Buonocore Daniela , Lanzafame Manuela , Najjaa Hanen , Lombardi Anita , Pagano Andrea , Dossena Maurizia , Verri Manuela , Arfa Abdelkarim Ben , Neffati Mohamed , Doria Enrico 
Published: May 2021

Abstract
Background
Hyperactivation of mechanistic target of rapamycin (mTOR) signaling pathway is involved in the regulation of cellular growth, proliferation, and more in general, is a common phenomenon in most types of cancers. Thus, natural substances targeting this pathway can be of great therapeutic potential in supporting the treatment of tumor patients. Rhus tripartita (Ucria) Grande is a plant growing in desertic areas which is traditionally used for the treatment of several diseases in Tunisia. In the present work, the biochemical profile of the main compounds present in the plant leaf extract was determined and the anti-leukemic potential of the plant extracts against acute monocytic leukaemia (AML) THP-1 cells was investigated.

Methods
After HPLC identification of some phenolic compounds present in the plant extract and the quantification of saponin content, the cytotoxic effect of Rhus tripartita extracts on THP-1 cell culture was evaluated using the colorimetric MTT assay for cell viability. THP-1 cells were incubated with medium containing the relative IC50 concentrations of total plant extract, saponin extract and some standard compounds (rutin (R); kaempferol (K); mixture of catechin, epicatechin, and epicatechin-gallate (CEEG); ellagic acid (EA). Finally, qRT-PCR and western blotting analysis were used to evaluate the effect of some flavonoids present in a crude extract of polyphenols and the total extract of saponins on cell survival and apoptosis.

Results
Analysis of expression level of some gene (PIK3CA, PTEN, AKT1, mTOR, EIF4E, RPS6KB1, and TSC1) involved in the mTOR pathway and the phosphorylation of S6 and AKT proteins allowed to observe that a total Rhus tripartita extract and some of the compounds found in the extract controls THP-1 cell proliferation and apoptosis via regulation of the PI3K-Akt-mTOR signaling pathway.

Conclusion
Rhus tripartita-induced inhibition of cell cycle and induction of apoptosis may involve the mTOR pathway. Therefore, Rhus tripartita extract may be a useful candidate as a natural anti-cancer drug to support the treatment of AML.
EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling
Authors: Liu Ze-Kun , Li Can , Zhang Ren-Yu , Wei Ding , Shang Yu-Kui , Yong Yu-Le , Kong Ling-Min , Zheng Nai-Shan , Liu Ke , Lu Meng , Liu Man , Hu Cai-Xia , Yang Xiao-Zhen , Chen Zhi-Nan , Bian Huijie 
Published: May 2021

AbstractBackgroundSomatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2.MethodsWhole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2−/−) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis.ResultsA new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway.ConclusionsIn our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.
Prevalence of HIV and HCV among injecting drug users in three selected WHO-EMRO countries: a meta-analysis
Authors: Shayan Shah Jahan , Nazari Rajab , Kiwanuka Frank 
Published: May 2021

AbstractBackgroundHIV and Hepatitis C Virus (HCV) infections are responsible for a significant burden of mortality and morbidity, particularly in developing countries. This study sought to determine the prevalence of HIV and Hepatitis C among injecting drug users in Afghanistan, Iran, and Pakistan.MethodsThis review conforms to the Preferred Reporting Guidelines for Systematic Reviews and Meta-Analysis (PRISMA) statement. Databases including PubMed, Scopus, Web of Science/Knowledge, SID.ir, and MAGIRAN were searched. Studies that were published from 2003 up to 2018 were considered for analysis. Studies were screened for inclusion in duplicate, and also, that data were narratively synthesized.ResultsWe report on data from 79 articles. The total number of participants in studies that assessed the prevalence of HIV among injecting drug users included 68,926 participants, while those from studies that assessed HCV prevalence were 23,016 participants. Overall HIV and HCV prevalence among injecting drug users in the three selected countries were 9.1% (95% CI 6.9–12.0%) and 48.3% (95% CI 43.9–52.7%), respectively. Iran had the highest HIV prevalence of 11.0% among injectable drug users (95% CI 8.4–14.2%), while Afghanistan had the lowest HIV prevalence of 3.1% (95% CI 1.5–6.3%) among three selected countries. In Pakistan, the prevalence of HIV was 8.6% (95% CI 4.8–15.0%). Regarding HCV prevalence, Pakistan had the highest while Afghanistan had the lowest, 54.4% (95% CI 33.5–73.9%) and 37.3% (95% CI 35.2–39.4%), respectively. HCV prevalence in Iran was 47.7% (95% CI 43.4–52.0%).ConclusionInjecting drug users form a special cohort of persons at risk of HIV and Hepatitis C infections. The prevalence of HIV and Hepatitis noted from our findings is significantly high. Awareness of the grave risk of spreading HIV and Hepatitis C associated with sharing needles is recommended among this sub-group of drug users.
MicroRNA-449a delays lung cancer development through inhibiting KDM3A/HIF-1α axis
Authors: Hu Shan , Cao Peng , Kong Kangle , Han Peng , Deng Yu , Li Fan , Zhao Bo 
Published: May 2021

Abstract
Background
It has been established that microRNA (miR)-449a is anti-tumorigenic in cancers, including lung cancer. Therefore, this study further explored miR-449a-mediated mechanism in lung cancer, mainly focusing on lysine demethylase 3A/hypoxia-induced factor-1α (KDM3A/HIF-1α) axis.

Methods
miR-449a, KDM3A and HIF-1α levels in lung cancer tissues and cell lines (A549, H1299 and H460) were measured. Loss- and gain-of-function assays were performed and then cell proliferation, cell cycle, apoptosis, invasion and migration were traced. The relationship between KDM3A, miR-449a and HIF-1α was verified. Tumor growth in vivo was also monitored.

Results
Both lung cancer tissues and cells exhibited reduced miR-449a and raised KDM3A and HIF-1α levels. miR-449a interacted with KDM3A; HIF-1α could bind with KDM3A. Up-regulating miR-449a hindered while suppressing miR-449a induced lung cancer development via mediating HIF-1α. Elevating KDM3A promoted cellular aggression while down-regulating KDM3A had the opposite effects. Up-regulating KDM3A or HIF-1α negated up-regulated miR-449a-induced effects on cellular growth in lung cancer. Restoring miR-449a impaired tumorigenesis in vivo in lung cancer.

Conclusion
It is eventually concluded that miR-449a delays lung cancer development through suppressing KDM3A/HIF-1α axis.
Cellular proliferation dynamics during regeneration in Syllis malaquini (Syllidae, Annelida)
Authors: Ribeiro Rannyele Passos , Egger Bernhard , Ponz-Segrelles Guillermo , Aguado M. Teresa 
Published: May 2021

Abstract
Background
In syllids (Annelida, Syllidae), the regenerative blastema was subject of many studies in the mid and late XXth century. This work on syllid regeneration showed that the blastema is developed by a process of dedifferentiation of cells near the wound, followed by their proliferation and redifferentiation (cells differentiate to the original cell type) or, in some specific cases, transdifferentiation (cells differentiate to a cell type different from the original). Up to date, participation of stem cells or pre-existing proliferative cells in the blastema development has never been observed in syllids. This study provides the first comprehensive description of Syllis malaquini’s regenerative capacity, including data on the cellular proliferation dynamics by using an EdU/BrdU labelling approach, in order to trace proliferative cells (S-phase cells) present before and after operation.

Results
Syllis malaquini can restore the anterior and posterior body from different cutting levels under experimental conditions, even from midbody fragments. Our results on cellular proliferation showed that S-phase cells present in the body before bisection do not significantly contribute to blastema development. However, in some specimens cut at the level of the proventricle, cells in S-phase located in the digestive tube before bisection participated in regeneration. Also, our results showed that nucleus shape allows to distinguish different types of blastemal cells as forming specific tissues. Additionally, simultaneous and sequential addition of segments seem to occur in anterior regeneration, while only sequential addition was observed in posterior regeneration. Remarkably, in contrast with previous studies in syllids, sexual reproduction was not induced during anterior regeneration of amputees lacking the proventricle, a foregut organ widely known to be involved in the stolonization control.

Conclusions
Our findings led us to consider that although dedifferentiation and redifferentiation might be more common, proliferative cells present before injury can be involved in regenerative processes in syllids, at least in some cases. Also, we provide data for comparative studies on resegmentation as a process that differs between anterior and posterior regeneration; and on the controversial role of the proventricle in the reproduction of different syllid lineages.
Radical treatment of severe open fractures of extremities by orthoplastic surgery: a 10-year retrospective study
Authors: Yang Zhao , Xu Chao , Zhu Yong-Gang , Li Jun , Wu Zi-Xiang , Zou Ji-Wei , Xue Bao-Bao , Miao Dan-Min , Shang Lei , Zhao Guang-Yue 
Published: May 2021

Abstract
Objective
This study aimed to retrospectively analyze clinical data of a series of patients with severe open fractures of extremities (Gustilo IIIb or IIIc), who achieved a satisfactory outcome through radical orthoplastic surgery, so as to provide a reference for determining the treatment of severe open fractures of extremities.

Methods
The clinical data of 41 consecutive patients with severe open fracture (Gustilo IIIb or IIIc) of the limb, who underwent successful surgical debridement, fixation, and soft tissue reconstruction in one stage between January 2008 and January 2019, were retrospectively reviewed. Postoperative indicators, including infection rate and union time, were acquired by a regular follow-up and analyzed.

Results
The mean (±SD) age of the patients was 38 ± 16 years. A total of 90 open fractures and severe soft tissue damages were analyzed. The soft tissue cover was achieved within 72 h. The overall rate of infection was 14.6% (6/41). Sex and the Mangled Extremity Severity Score were associated with infection. The median union time of 40 patients (one amputation) was 32 weeks.

Conclusion
The overall rate of infection exhibited a lower tendency in this study compared with previous studies on high-grade open fractures following a two-stage orthopedic approach. The consequence of infection rate and union time was similar to that in previous studies. These results indicated that the single-stage radical orthoplastic treatment was an effective and reliable option for reconstructing severe open fractures.
Integrated transcriptomics explored the cancer-promoting genes CDKN3 in esophageal squamous cell cancer
Authors: Wang Wanpeng , Liao Kai , Guo Hao Chun , Zhou Suqin , Yu Ran , Liu Yanyan , Pan Yan , Pu Juan 
Published: May 2021

Abstract
Background and objectives
Each individual studies is limited to multi-factors and potentially lead to a significant difference of results among them. The present study aim to explore the critical genes related to the development of Esophageal squamous cell carcinoma (ESCC) by integrated transcriptomics and to investigate the clinical significance by experimental validation.

Methods
Datasets of protein-coding genes expression which involved in ESCC were downloaded from Gene Expression Omnibus (GEO) database. The “Robustrankaggreg” package in language was used for data integration, and the different expression genes (DEGs) were identified based the cut-off criteria as follows: adjust p-value < 0.05, |fold change (FC)| ≥ 1.5; The protein expression of seed gene in 184 cases of primary ESCC tissues and 50 tumor adjacent normal tissues (at least 5 cm away from the tumor, and defind as the controls) were detected by immunohistochemistry; The relationship between the expression level of seed genes and clinical parameter were analyze. Enumeration data were represented by frequency or percentage (%) and were tested by x2 test. The P value of less than 0.05 was considered statistically significant.

Results
A total of 244 DEGs were identified by comparing gene expression patterns between ESCC patients and the controls based on integrating dataset of GSE77861, GSE77861, GSE100942, GSE26886, GSE17351, GSE38129, GSE33426, GSE20347 and GSE23400; The Cyclin-dependent kinase inhibitor 3 (CDKN3) were identified the top 1 seed gene of top cluster by use of protein-protein Interaction network and plug-in Molecular Complex Detection; The level of CDKN3 mRNA was significantly increased in ESCC patients compared to controls; The positive expression rate of CDKN3 protein in ESCC tissue samples was 32 and 61.4% in control, respectively. The correlations between the expression level of CDKN3 and lymph node metastasis or clinical staging of ESCC patients are statistically significant.

Conclusion
Integrated transcriptomics is an efficient approach to system biology. By this procedure, our study improved the understanding of the transcriptome status of ESCC.
A case of thyroid storm caused by Graves’ disease misdiagnosed as panic attack due to panic disorder
Authors: Yasuda Manabu , Kumakura Jun , Oka Kiyonori , Fukuda Kazuhito 
Published: May 2021

Abstract
Background
Graves’ disease is characterized by hyperthyroidism and its symptoms often overlap with those of panic disorder, which may make it difficult to distinguish between the two conditions. In this report, we describe how proper diagnosis of thyroid disease in patients with mental illness can lead to appropriate treatment.

Case presentation
We encountered a 34-year-old woman in whom thyroid crisis from Graves’ disease was misdiagnosed as panic attack. The patient was being managed as a case of panic disorder and bipolar disorder in a psychiatric outpatient setting. About 6 months before presentation she had lost about 16 kg in weight, and a month before presentation she developed several unpleasant symptoms as her condition worsened. Several weeks before she had had severe palpitations, tachycardia, and discomfort in her throat. She became unable to eat solids, ate only yogurt and gelatin, and felt it difficult to take psychiatric drugs.
She visited our emergency outpatient department on a Sunday morning, presenting with nausea, severe tachycardia, fever, and restlessness with anxiety. We treated her as panic disorder with fever, but noted proptosis and considered the possibility of Graves’ disease. Thyroid function tests were performed even though data from her clinic was not available because it was a weekend.
Because there was no improvement in her condition after her first visit, she returned to our hospital early the next morning. We had misdiagnosed her as having severe panic attacks due to panic disorder, and after a diazepam injection had allowed her to go home.
Later that day, the thyroid function test results became available, and her symptoms and the results strongly indicated a thyroid storm. The endocrinology department was consulted immediately, and she was referred for hospitalization the next day. During hospitalization, she was treated with steroid and radioactive iodine therapy and was discharged from hospital in 3 weeks.

Conclusion
Psychiatrists and doctors engaged in psychosomatic medicine need to consider the possibility of severe hyperthyroidism as a differential diagnosis of panic disorder.
Is postoperative non-weight-bearing necessary? INWN Study protocol for a pragmatic randomised multicentre trial of operatively treated ankle fracture
Authors: Khojaly Ramy , Mac Niocaill Ruairí , Shahab Muhammad , Nagle Matthew , Taylor Colm , Rowan Fiachra E. , Cleary May 
Published: May 2021

Abstract
Background
Postoperative management regimes vary following open reduction and internal fixation (ORIF) of unstable ankle fractures. There is an evolving understanding that extended periods of immobilisation and weight-bearing limitation may lead to poorer clinical outcomes. Traditional non-weight-bearing cast immobilisation may prevent loss of fixation, and this practice continues in many centres. The purpose of this trial is to investigate the safety and efficacy of immediate weight-bearing (IWB) and range of motion (ROM) exercise regimes following ORIF of unstable ankle fractures with a particular focus on functional outcomes and complication rates.

Methods
A pragmatic randomised controlled multicentre trial, comparing IWB in a walking boot and ROM within 24 h versus non-weight-bearing (NWB) and immobilisation in a cast for 6 weeks, following ORIF of all types of unstable adult ankle fractures (lateral malleolar, bimalleolar, trimalleolar with or without syndesmotic injury) is proposed. All patients presenting to three trauma units will be included. The exclusion criteria will be skeletal immaturity and tibial plafond fractures. The three institutional review boards have granted ethical approval. The primary outcome measure will be the functional Olerud-Molander Ankle Score (OMAS). Secondary outcomes include wound infection (deep and superficial), displacement of osteosynthesis, the full arc of ankle motion (plantar flexion and dorsal flection), RAND-36 Item Short Form Survey (SF-36) scoring, time to return to work and postoperative hospital length of stay. The trial will be reported in accordance with the CONSORT statement for reporting a pragmatic trial, and this protocol will follow the SPIRIT guidance.

Discussion
Traditional management of operatively treated ankle fractures includes an extended period of non-weight-bearing. There is emerging evidence that earlier weight-bearing may have equivocal outcomes and favourable patient satisfaction but higher wound-related complications. These studies often preclude more complicated fracture patterns or patient-related factors. To our knowledge, immediate weight-bearing (IWB) following ORIF of all types of unstable ankle fractures has not been investigated in a controlled prospective manner in recent decades. This pragmatic randomised-controlled multicentre trial will investigate immediate weight-bearing following ORIF of all ankle fracture patterns in the usual care condition. It is hoped that these results will contribute to the modern management of ankle fractures.

Trial registration
ISRCTN Registry ISRCTN76410775. Retrospectively registered on 30 June 2019.
Spatio-temporal modelling of Culicoides Latreille (Diptera: Ceratopogonidae) populations on Reunion Island (Indian Ocean)
Authors: Grimaud Yannick , Tran Annelise , Benkimoun Samuel , Boucher Floriane , Esnault Olivier , Cêtre-Sossah Catherine , Cardinale Eric , Garros Claire , Guis Hélène 
Published: May 2021

Abstract
Background
Reunion Island regularly faces outbreaks of bluetongue and epizootic hemorrhagic diseases, two insect-borne orbiviral diseases of ruminants. Hematophagous midges of the genus Culicoides (Diptera: Ceratopogonidae) are the vectors of bluetongue (BTV) and epizootic hemorrhagic disease (EHDV) viruses. In a previous study, statistical models based on environmental and meteorological data were developed for the five Culicoides species present in the island to provide a better understanding of their ecology and predict their presence and abundance. The purpose of this study was to couple these statistical models with a Geographic Information System (GIS) to produce dynamic maps of the distribution of Culicoides throughout the island.

Methods
Based on meteorological data from ground weather stations and satellite-derived environmental data, the abundance of each of the five Culicoides species was estimated for the 2214 husbandry locations on the island for the period ranging from February 2016 to June 2018. A large-scale Culicoides sampling campaign including 100 farms was carried out in March 2018 to validate the model.

Results
According to the model predictions, no husbandry location was free of Culicoides throughout the study period. The five Culicoides species were present on average in 57.0% of the husbandry locations for C. bolitinos Meiswinkel, 40.7% for C. enderleini Cornet & Brunhes, 26.5% for C. grahamii Austen, 87.1% for C. imicola Kieffer and 91.8% for C. kibatiensis Goetghebuer. The models also showed high seasonal variations in their distribution. During the validation process, predictions were acceptable for C. bolitinos, C. enderleini and C. kibatiensis, with normalized root mean square errors (NRMSE) of 15.4%, 13.6% and 16.5%, respectively. The NRMSE was 27.4% for C. grahamii. For C. imicola, the NRMSE was acceptable (11.9%) considering all husbandry locations except in two specific areas, the Cirque de Salazie—an inner mountainous part of the island—and the sea edge, where the model overestimated its abundance.

Conclusions
Our model provides, for the first time to our knowledge, an operational tool to better understand and predict the distribution of Culicoides in Reunion Island. As it predicts a wide spatial distribution of the five Culicoides species throughout the year and taking into consideration their vector competence, our results suggest that BTV and EHDV can circulate continuously on the island. As further actions, our model could be coupled with an epidemiological model of BTV and EHDV transmission to improve risk assessment of Culicoides-borne diseases on the island.

Graphical Abstract