bluuebunny/crossref_metadata_2025_split huggingface dataset:
A non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate cancer
Authors: Fletcher C. E. , Deng L. , Orafidiya F. , Yuan W. , Lorentzen M. P. G. S. , Cyran O. W. , Varela-Carver A. , Constantin T. A. , Leach D. A. , Dobbs F. M. , Figueiredo I. , Gurel B. , Parkes E. , Bogdan D. , Pereira R. R. , Zhao S. G. , Neeb A. , Issa F. , Hester J. , Kudo H. , Liu Y. , Philippou Y. , Bristow R. , Knudsen K. , Bryant R. J. , Feng F. Y. , Reed S. H. , Mills I. G. , de Bono J. , Bevan C. L. 
Published: March 2022

AbstractBackgroundmiR-346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)-linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR-346 on DNA damage, and its potential as a therapeutic agent.MethodsRNA-IP, RNA-seq, RNA-ISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplification-free, single nucleotide-resolution genome-wide mapping of DNA breaks (INDUCE-seq).ResultsmiR-346 induces rapid and extensive DNA damage in PC cells - the first report of microRNA-induced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, R-loop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR-346 also interacts with genome-protective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poor PC clinical outcomes and increased DDR in biopsy RNA-seq studies. In contrast, miR-346 is associated with improved PC survival.INDUCE-seq reveals that miR-346-induced DSBs occur preferentially at binding sites of the most highly-transcriptionally active transcription factors in PC cells, including c-Myc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNA-seq reveals widespread miR-346 and shNORAD dysregulation of DNA damage, replication and cell cycle processes.NORAD drives target-directed miR decay (TDMD) of miR-346 as a novel genome protection mechanism: NORAD silencing increases mature miR-346 levels by several thousand-fold, and WT but not TDMD-mutant NORAD rescues miR-346-induced DNA damage. Importantly, miR-346 sensitises PC cells to DNA-damaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a monotherapy in vivo, indicating that targeting miR-346:NORAD balance is a valid therapeutic strategy.ConclusionsA balancing act between miR-346 and NORAD regulates DNA damage and repair in PC. miR-346 may be particularly effective as a therapeutic in the context of decreased NORAD observed in advanced PC, and in transcriptionally-hyperactive cancer cells.
Intended preoperative trans-arterial embolization for large hepatocellular carcinoma: a retrospective cohort study
Authors: Saito Ryo , Amemiya Hidetake , Hosomura Naohiro , Kawaida Hiromichi , Shoda Katsutoshi , Furuya Shinji , Akaike Hidenori , Kawaguchi Yoshihiko , Inoue Shingo , Kono Hiroshi , Ichikawa Daisuke 
Published: March 2022

Abstract
Background
Generally, a large tumor size of hepatocellular carcinoma (HCC) is associated with poor visibility and uncertainty in the surgical field which results in increased surgical difficulty as well as unfavorable postoperative outcomes. We performed intended preoperative trans-arterial embolization (TAE) in patients with a large HCC. In this study, we investigated the oncological significance of intended preoperative TAE for a large HCC, using a comparison between patients with and without TAE, and detailed analyses for pre- and post-TAE status.

Methods
A total of 411 patients who underwent hepatectomy for primary HCC at the University of Yamanashi Hospital between January 2007 and December 2018 were included in this study. The patients were divided into two groups: patients with larger HCCs (≥50 mm, n=51) and those with smaller HCC (<50 mm, n=360) according to the size of their HCCs. Comparison of clinicopathological features between these groups and clinical outcomes between the TAE and non-TAE groups were compared. In addition, a detailed analysis of each case in the TAE group was conducted, comparing clinicopathological factors between pre- and post-TAE status.

Results
The clinical unfavorable short- and long-term outcomes of patients with large HCCs (≥50 mm) were revealed compared to those with small HCCs (<50 mm). The prognostic analyses showed that a large tumor size and increased tumor markers, multiple tumor numbers, and others were adverse prognostic factors, and vascular invasions and residual tumors were included in the multivariate analysis.
Further detailed analyses revealed that the average rates of change in tumor size and tumor shrinkage after TAE were − 48.6±35.6 mm and − 30.7±17.0%, respectively. Pathological high necrotic changes in the tumor, after multiple-times TAE aiming to a better effect, were related to a better prognosis in patients with large HCC. Poor prognostic factors became less common in patients who underwent intended preoperative TAE, and these patients had better prognoses.

Conclusions
The large tumor size of HCC is associated with unfavorable outcomes; the intended preoperative TAE for large HCC patients performed multiple times aiming to affect the tumor as much as possible might improve their prognoses.
Role of Chemerin/ChemR23 axis as an emerging therapeutic perspective on obesity-related vascular dysfunction
Authors: Xie Yingying , Liu Ling 
Published: March 2022

AbstractSufficient epidemiological investigations demonstrate that there is a close correlation between obesity and vascular dysfunction. Nevertheless, specific mechanisms underlying this link remain currently unclear. Given the crucial and decisive role of vascular dysfunction in multitudinous diseases, various hypotheses had been proposed and numerous experiments were being carried out. One recognized view is that increased adipokine secretion following the expanded mass of white adipose tissue due to obesity contributes to the regulation of vascular function. Chemerin, as a neo-adipokine, whose systemic level is elevated in obesity, is believed as a regulator of adipogenesis, inflammation, and vascular dysfunction via binding its cell surface receptor, chemR23. Hence, this review aims to focus on the up-to-date proof on chemerin/chemR23 axis-relevant signaling pathways, emphasize the multifarious impacts of chemerin/chemR23 axis on vascular function regulation, raise certain unsettled questions to inspire further investigations, and explore the therapeutic possibilities targeting chemerin/chemR23.
CircESRP1 enhances metastasis and epithelial–mesenchymal transition in endometrial cancer via the miR-874-3p/CPEB4 axis
Authors: Shi Rui , Zhang Wei , Zhang Jun , Yu Zhicheng , An Lanfen , Zhao Rong , Zhou Xing , Wang Ziwei , Wei Sitian , Wang Hongbo 
Published: March 2022

AbstractBackgroundMetastasis is critical for endometrial cancer (EC) progression and prognosis. Accumulating evidence suggests that circular RNAs (circRNAs) can operate as independent functional entities. However, the functional regulatory mechanisms of circRNAs in EC remain unclear.MethodsThe levels of circESRP1, miR-874-3p, and CPEB4 mRNA in EC tissues and cells were determined by qRT-PCR. Sanger sequencing, PCR with divergent primers, an actinomycin D assay, and RNase R treatment were applied to verify the circular properties. Fluorescence in situ hybridization (FISH) and nuclear-cytoplasmic fractionation were used to determine the localization of circESRP1. CCK-8, EdU incorporation, colony formation, Transwell, and wound healing assays were applied to assess the effects of circESRP1 on cell proliferation, migration, and invasion. The mutual regulatory mechanism of ceRNAs was investigated using dual-luciferase reporter, RNA pulldown, RNA immunoprecipitation (RIP), and Western blot assays. The biological effects were further validated in vivo in nude mouse xenograft models.ResultscircESRP1 was highly expressed in EC tissues and cells and was mainly localized in the cytoplasm. Silencing circESRP1 inhibited the proliferation, migration, and invasion of EC cells in vitro and in vivo; however, overexpression of circESRP1 had the opposite effects. Mechanistically, circESRP1 sponged miR-874-3p to upregulate CPEB4 expression and ultimately contribute to EC cell proliferation and metastasis. Furthermore, circESRP1 regulated tumour growth in xenograft models.ConclusionsCircESRP1 can interact with miR-874-3p to regulate EMT in endometrial cancer via the miR-874-3p/CPEB4 axis. CircESRP1 may serve as a promising therapeutic target for endometrial cancer.
Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)
Authors: Haffke Milan , Freitag Helma , Rudolf Gordon , Seifert Martina , Doehner Wolfram , Scherbakov Nadja , Hanitsch Leif , Wittke Kirsten , Bauer Sandra , Konietschke Frank , Paul Friedemann , Bellmann-Strobl Judith , Kedor Claudia , Scheibenbogen Carmen , Sotzny Franziska 
Published: March 2022

Abstract
Background
Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.

Methods
We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.

Results
Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.

Conclusion
A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.
Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response
Authors: Ashrafizadeh Milad , Paskeh Mahshid Deldar Abad , Mirzaei Sepideh , Gholami Mohammad Hossein , Zarrabi Ali , Hashemi Farid , Hushmandi Kiavash , Hashemi Mehrdad , Nabavi Noushin , Crea Francesco , Ren Jun , Klionsky Daniel J. , Kumar Alan Prem , Wang Yuzhuo 
Published: March 2022

AbstractProstate cancer is a leading cause of death worldwide and new estimates revealed prostate cancer as the leading cause of death in men in 2021. Therefore, new strategies are pertinent in the treatment of this malignant disease. Macroautophagy/autophagy is a “self-degradation” mechanism capable of facilitating the turnover of long-lived and toxic macromolecules and organelles. Recently, attention has been drawn towards the role of autophagy in cancer and how its modulation provides effective cancer therapy. In the present review, we provide a mechanistic discussion of autophagy in prostate cancer. Autophagy can promote/inhibit proliferation and survival of prostate cancer cells. Besides, metastasis of prostate cancer cells is affected (via induction and inhibition) by autophagy. Autophagy can affect the response of prostate cancer cells to therapy such as chemotherapy and radiotherapy, given the close association between autophagy and apoptosis. Increasing evidence has demonstrated that upstream mediators such as AMPK, non-coding RNAs, KLF5, MTOR and others regulate autophagy in prostate cancer. Anti-tumor compounds, for instance phytochemicals, dually inhibit or induce autophagy in prostate cancer therapy. For improving prostate cancer therapy, nanotherapeutics such as chitosan nanoparticles have been developed. With respect to the context-dependent role of autophagy in prostate cancer, genetic tools such as siRNA and CRISPR-Cas9 can be utilized for targeting autophagic genes. Finally, these findings can be translated into preclinical and clinical studies to improve survival and prognosis of prostate cancer patients.Graphical abstract
Aquatain® causes anti-oviposition, egg retention and oocyte melanization and triggers female death in Aedes aegypti
Authors: Dieng Hamady , McLean Storm , Stradling Holly , Morgan Cole , Gordon Malik , Ebanks Whitney , Ebanks Zoila , Wheeler Alan 
Published: March 2022

AbstractBackgroundIn arboviral disease systems where the virus can be transmitted from male to female vectors and from one generation to the next, targeting the female (especially when she is gravid) can help alter the persistence of the virus in nature and its transmission. A typical example is Aedes aegypti, which has become unmanageable due to the development of insecticide resistance. Despite evidence that monomolecular surface films prevent the selection of genetic resistance, their potential in Aedes vector control remains largely unexplored.MethodsWe examined the oviposition, egg retention, oocyte melanization, and female mortality of the Cayman Islands strain of Ae. aegypti, using choice (balanced and unbalanced) and no-choice bioassays involving Aquatain® Mosquito Formulation (AMF; Aquatain Products Pty Ltd.), a polydimethylsiloxane–based liquid used for mosquito control.ResultsWhen presented with similar opportunities to oviposit in two sites treated with AMF and two other sites with untreated water (control), egg deposition rates were significantly higher in the untreated water sites than in the AMF-treated sites (P < 0.05). We also observed a matching pattern of egg deposition preference in environments with more options in terms of AMF-treated sites. Females laid significantly more eggs when water was the only available medium than when all sites were treated with AMF (P < 0.05). Also, significantly more mature eggs were withheld in the AMF no-choice environment than in the no-choice test involving only water (P < 0.05). Internal oocyte melanization was not observed in females from the oviposition arenas with the lowest AMF presence (equal-choice and water-based no-choice); in contrast, this physiological response intensified as the number of AMF-treated sites increased. Female death occurred at high rates in AMF-treated environments, and this response increased with the increasing presence of such egg deposition sites.ConclusionsThis study demonstrated that AMF acted as a deterrent signal to ovipositing Ae. aegypti and as an indirect adulticide. These results suggest that AMF may be a promising control tool against the dengue vector, and this warrants further evaluation under field settings.Graphical Abstract
Genome-wide association studies identify novel genetic loci for epigenetic age acceleration among survivors of childhood cancer
Authors: Dong Qian , Song Nan , Qin Na , Chen Cheng , Li Zhenghong , Sun Xiaojun , Easton John , Mulder Heather , Plyler Emily , Neale Geoffrey , Walker Emily , Li Qian , Ma Xiaotu , Chen Xiang , Huang I-Chan , Yasui Yutaka , Ness Kirsten K. , Zhang Jinghui , Hudson Melissa M. , Robison Leslie L. , Wang Zhaoming 
Published: March 2022

AbstractBackgroundIncreased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA.MethodsGenome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability.ResultsFor EAA-Horvath, a genome-wide significant association was mapped to theSELPgene with the strongest SNP rs732314 (meta-GWAS:β=0.57,P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS:β=0.97 vs. 0.51,I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31,I2=66.3%). For EAA-Hannum, an association was mapped to theHLAlocus with the strongest SNP rs28366133 (meta-GWAS:β=0.78,P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09,P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21,P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge.ConclusionsWe identified novel genetic variants in theSELPgene andHLAregion associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.
The association of sleep patterns and depressive symptoms in medical students: a cross-sectional study
Authors: Dudo Katrin , Ehring Emilia , Fuchs Stephan , Herget Sabine , Watzke Stefan , Unverzagt Susanne , Frese Thomas 
Published: March 2022

Abstract
Objective
Mental health is a fundamental aspect in ensuring the stable and successful professional life of future physicians. Depressive symptoms can negatively affect the work-life-balance and efficiency at work of medical students.
To date, there have been very few studies involving medical students that examine the association between single sleep characteristics and the outcome of the Beck Depression Inventory-II score. Therefore, the aim of the present study is to investigate this possible association. A classroom survey using socio-demographic characteristics, the Beck Depression Inventory-II, and the Pittsburgh Sleep Quality Index was conducted amongst students at a German medical school from December 2017 to September 2018. Data analysis was performed with descriptive statistics and binary logistic regression.

Results
Of the students surveyed, 19% showed depressive symptoms with a Beck Depression Inventory-II score over 13 and 42% of these cases were moderate or severe. The occurrence of relevant depressive symptoms was associated with lower sleep quality, higher sleep latency, and the consumption of sleeping pills. In general, female students and students from abroad had a higher risk of depressive symptoms. Addressing these relevant findings in medical school can increase awareness of mental health.
Evaluation of multi-sample 16S ribosomal DNA sequencing for the diagnosis of postoperative bone and joint infections during antimicrobial treatment
Authors: Wallander Katja , Vondracek Martin , Giske Christian G. 
Published: March 2022

Abstract
Objectives
Clinicians worldwide struggle to identify the bacterial aetiology of bone and joint infections. Failure to unequivocally identify the pathogen is linked to poor clinical outcomes. We explored the added value of analysing multiple samples per patient with 16S ribosomal DNA (16S rDNA) sequencing in diagnosing postoperative bone and joint infections. All patients had received antimicrobials prior to sampling, and false-negative cultures could be suspected. Bone biopsies obtained from patients with postoperative bone and joint infections for cultures were also subjected to 16S rDNA sequencing.

Results
In 5/28 infectious episodes, sequencing identified the causative organism of the infection when cultures failed. In 8/28 episodes, the methods led to different results, potentially leading to different antimicrobial choices. The analysis of multiple samples per patient helped rule out potential contaminating pathogens. We conclude that 16S rDNA sequencing has diagnostic value for patients receiving antibiotic treatment. We regard the method as a complement to culturing when the cultures are negative. Multiple samples per patient should be analysed to determine the clinical significance of positive findings.
RNA-Seq analysis of gene expression in 25 cases of canine lymphoma undergoing CHOP chemotherapy
Authors: Mee Miles W. , Faulkner Sydney , Wood Geoffrey A. , Woods J. Paul , Bienzle Dorothee , Coomber Brenda L. 
Published: March 2022

AbstractObjectivesCanine lymphoma, the most common hematological cancer in dogs, shares many molecular and clinical characteristics with human Non-Hodgkin lymphoma (NHL). The standard treatment for canine lymphoma is “CHOP” multiagent chemotherapy protocol consisting of Cyclophosphamide, Doxorubicin (Hydroxydaunorubicin), Vincristine (Oncovin™), and Prednisone. Approximately 70–85% of patients treated with CHOP achieve clinical remission. However, duration of remission varies and the majority of dogs eventually relapse. To identify possible biomarkers for patients failing to achieve remission, we performed RNA-Seq analysis on 25 cases of canine lymphoma obtained prior the start of their CHOP therapy regime and assessed gene expression associated with patient progression free survival (PFS).Data descriptionThe data consists of (1) raw RNA-Seq reads in 75 bp fastq format from fine needle aspirate samples of enlarged lymph nodes from canine patients with naturally occurring lymphoma; (2) Fragments Per Kilobase Million (FPKM) values for each sample; (3) raw transcript counts for each sample; (4) anonymized patient details including PFS; (5) heat map of gene expression and (6) Cox proportional hazard analysis showing significantly expressed genes. These data may be useful for comparative analysis of gene expression in human NHL and analysis of gene expression associated with disease outcome in canine lymphoma.