bluuebunny/crossref_metadata_2025_split huggingface dataset:
circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis
Authors: Hu Chonghui , Xia Renpeng , Zhang Xiang , Li Tingting , Ye Yuancheng , Li Guolin , He Rihua , Li Zhihua , Lin Qing , Zheng Shangyou , Chen Rufu 
Published: January 2022

Abstract
Background
Cancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which CAFs promote chemotherapy resistance remains unexplored. Here, we explored the role of circRNAs in CAF-induced GEM resistance in PDAC.

Methods
circRNA sequencing and quantitative real-time PCR (qRT–PCR) were utilized to screen CAF-specific circRNAs. The effects of CAF circFARP1 expression on GEM resistance in tumor cells were assessed in vitro and in vivo. RNA-seq, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays were used to screen the downstream target and underlying mechanism of circFARP1.

Results
circFARP1 (hsa_circ_0002557), a CAF-specific circRNA, was positively correlated with GEM chemoresistance and poor survival in an advanced PDAC cohort. Silencing or overexpressing circFARP1 in CAFs altered the ability of CAFs to induce tumor cell stemness and GEM resistance via leukemia inhibitory factor (LIF). Mechanistically, we found that circFARP1 directly binds with caveolin 1 (CAV1) and blocks the interaction of CAV1 and the E3 ubiquitin-protein ligase zinc and ring finger 1 (ZNRF1) to inhibit CAV1 degradation, which enhances LIF secretion. In addition, circFARP1 upregulated LIF expression by sponging miR-660-3p. Moreover, high circFARP1 levels were positively correlated with elevated serum LIF levels in PDAC and poor patient survival. Decreasing circFARP1 levels and neutralizing LIF significantly suppressed PDAC growth and GEM resistance in patient-derived xenograft models.

Conclusions
The circFARP1/CAV1/miR-660-3p/LIF axis is critical for CAF-induced GEM resistance in PDAC. Hence, circFARP1 may be a potential therapeutic target for PDAC.
Peripheral magnetic theta burst stimulation to muscles can effectively reduce spasticity: a randomized controlled trial
Authors: El Nahas Nevine , Kenawy Fatma Fathalla , Abd Eldayem Eman Hamid , Roushdy Tamer M. , Helmy Shahinaz M. , Akl Ahmed Zaki , Ashour Aya Ahmed , Emara Tamer H. , Moawad Marwa Mohamed , Amin Randa M. , Elbokl Ahmed M. 
Published: January 2022

Abstract
Background
Spasticity is a common complication of many neurological diseases and despite contributing much disability; the available therapeutic options are limited. Peripheral magnetic stimulation is one promising option. In this study, we investigated whether peripheral intermittent theta burst stimulation (piTBS) will reduce spasticity when applied directly on spastic muscles.

Methods
In this sham-controlled study, eight successive sessions of piTBS were applied directly to spastic muscles with supra threshold intensity. Assessment was done by modified Ashworth scale (mAS) and estimated Botulinum toxin dose (eBTD) at baseline and after the 8th session in both active and sham groups.

Results
A total of 120 spastic muscles of 36 patients were included in the analysis. Significant reduction of mAS and eBTD was found in the active compared to sham group (p < 0.001). The difference in mAS was also significant when tested in upper limb and lower limb subgroups. The degree of reduction in mAS was positively correlated with the baseline scores in the active group.

Conclusion
piTBS could be a promising method to reduce spasticity and eBTD. It consumes less time than standard high frequency protocols without compromising treatment efficacy.
Trial registration: Clinical trial registry number: PACTR202009622405087. Retrospectively Registered 14th September, 2020.
In situ analysis of hepatitis B virus (HBV) antigen and DNA in HBV-induced hepatocellular carcinoma
Authors: Zheng Ye , Xu Mingzhu , Zeng Dong , Tong Haitao , Shi Yuhan , Feng Yanling , Zhang Xiaonan 
Published: January 2022

Abstract
Aims
Hepatitis B Virus (HBV) infection is the major risk factor for hepatocellular carcinoma (HCC) in East Asia. Here we aimed to further investigate the abundance of viral antigen and DNA within HBV-related HCC and surrounding tissues at histological level.

Method
In addition to routine histopathology, in situ hybridization (ISH) of HBV DNA and immunohistochemistry (IHC) of HBsAg were performed in tissues from 131 HBsAg-positive HCC patients undergoing liver resection. Serum α-fetoprotein together with basic biochemical and immunological parameter was also measured.

Results
Overall, the ISH of HBV DNA and IHC of HBsAg showed 31.3% and 92.9% positive rate respectively (p < 0.0001). The level of correlation between these two markers was much more significant in tumor (p < 0.0001) than in tumor-surrounding tissue (p = 0.01). HBsAg exhibited a much higher positive rate in tumor-adjacent tissue than in tumor tissue (86.6% versus 29.9%, p < 0.0001) with significantly different staining pattern. By contrast, the positive rate of HBV DNA ISH was comparable in tumor and surrounding tissue (17.6% versus 22.9%, p = 0.36). Yet the HBV DNA signal in tumor tissue showed predominant nuclear localization (87.0%) whereas staining pattern in adjacent tissue was mixed (43.3% nuclear localization, p = 0.0015). Finally, no significant association between intra-tumor HBV DNA/HBsAg positivity and major histological markers (microvascular invasion, tumor differentiation, etc.) or recurrence after surgery was observed.

Conclusions
These data confirmed the largely integrated state of HBV DNA, weaker expression and altered localization of surface antigen in tumor compared with surrounding tissue. The strikingly different prevalence and localization of HBsAg and HBV DNA reflected the complex and heterogeneous mechanisms leading to HBV-induced tumorigenesis.
HairNet: a deep learning model to score leaf hairiness, a key phenotype for cotton fibre yield, value and insect resistance
Authors: Rolland Vivien , Farazi Moshiur R. , Conaty Warren C. , Cameron Deon , Liu Shiming , Petersson Lars , Stiller Warwick N. 
Published: January 2022

AbstractBackgroundLeaf hairiness (pubescence) is an important plant phenotype which regulates leaf transpiration, affects sunlight penetration, and provides increased resistance or susceptibility against certain insects. Cotton accounts for 80% of global natural fibre production, and in this crop leaf hairiness also affects fibre yield and value. Currently, this key phenotype is measured visually which is slow, laborious and operator-biased. Here, we propose a simple, high-throughput and low-cost imaging method combined with a deep-learning model, HairNet, to classify leaf images with great accuracy.ResultsA dataset of$$\sim $$∼ 13,600 leaf images from 27 genotypes of Cotton was generated. Images were collected from leaves at two different positions in the canopy (leaf 3 & leaf 4), from genotypes grown in two consecutive years and in two growth environments (glasshouse & field). This dataset was used to build a 4-part deep learning model called HairNet. On the whole dataset, HairNet achieved accuracies of 89% per image and 95% per leaf. The impact of leaf selection, year and environment on HairNet accuracy was then investigated using subsets of the whole dataset. It was found that as long as examples of the year and environment tested were present in the training population, HairNet achieved very high accuracy per image (86–96%) and per leaf (90–99%). Leaf selection had no effect on HairNet accuracy, making it a robust model.ConclusionsHairNet classifies images of cotton leaves according to their hairiness with very high accuracy. The simple imaging methodology presented in this study and the high accuracy on a single image per leaf achieved by HairNet demonstrates that it is implementable at scale. We propose that HairNet replaces the current visual scoring of this trait. The HairNet code and dataset can be used as a baseline to measure this trait in other species or to score other microscopic but important phenotypes.
Is postoperative cognitive decline after cardiac surgery associated with plasma beta amyloid 1–42 levels?
Authors: Požgain Zrinka , Dulić Grgur , Kondža Goran , Bogović Siniša , Šerić Ivan , Hil Dejan , Trogrlić Bojan , Bednjanić Ana , Perković-Kovačević Marina , Šahinović Ines 
Published: January 2022

AbstractBackgroundPostoperative cognitive decline following cardiac surgery is one of the frequently reported complications affecting postoperative outcome, characterized by impairment of memory or concentration. The aetiology is considered multifactorial and the research conducted so far has presented contradictory results. The proposed mechanisms to explain the cognitive decline associated with cardiac surgery include the neurotoxic accumulation of β-amyloid (Aβ) proteins similar to Alzheimer's disease. The comparison of coronary artery bypass grafting procedures concerning postoperative cognitive decline and plasmatic Aβ1-42 concentrations has not yet been conducted.MethodsThe research was designed as a controlled clinical study of patients with coronary artery disease undergoing surgical myocardial revascularization with or without the use of a cardiopulmonary bypass machine. All patients completed a battery of neuropsychological tests and plasmatic Aβ1-42 concentrations were collected.ResultsThe neuropsychological test results postoperatively were significantly worse in the cardiopulmonary bypass group and the patients had larger shifts in the Aβ1-42 preoperative and postoperative values than the group in which off-pump coronary artery bypass was performed.ConclusionsThe conducted research confirmed the earlier suspected association of plasmatic Aβ1-42 concentration to postoperative cognitive decline and the results further showed that there were less changes and lower concentrations in the off-pump coronary artery bypass group, which correlated to less neurocognitive decline. There is a lot of clinical contribution acquired by this research, not only in everyday decision making and using amyloid proteins as biomarkers, but also in the development and application of non-pharmacological and pharmacological neuroprotective strategies.
Omega-6 sparing effects of parenteral lipid emulsions—an updated systematic review and meta-analysis on clinical outcomes in critically ill patients
Authors: Notz Quirin , Lee Zheng-Yii , Menger Johannes , Elke Gunnar , Hill Aileen , Kranke Peter , Roeder Daniel , Lotz Christopher , Meybohm Patrick , Heyland Daren K. , Stoppe Christian 
Published: January 2022

AbstractBackgroundParenteral lipid emulsions in critical care are traditionally based on soybean oil (SO) and rich in pro-inflammatory omega-6 fatty acids (FAs). Parenteral nutrition (PN) strategies with the aim of reducing omega-6 FAs may potentially decrease the morbidity and mortality in critically ill patients.MethodsA systematic search of MEDLINE, EMBASE, CINAHL and CENTRAL was conducted to identify all randomized controlled trials in critically ill patients published from inception to June 2021, which investigated clinical omega-6 sparing effects. Two independent reviewers extracted bias risk, treatment details, patient characteristics and clinical outcomes. Random effect meta-analysis was performed.Results1054 studies were identified in our electronic search, 136 trials were assessed for eligibility and 26 trials with 1733 critically ill patients were included. The median methodologic score was 9 out of 14 points (95% confidence interval [CI] 7, 10). Omega-6 FA sparing PN in comparison with traditional lipid emulsions did not decrease overall mortality (20 studies; risk ratio [RR] 0.91; 95% CI 0.76, 1.10;p = 0.34) but hospital length of stay was substantially reduced (6 studies; weighted mean difference [WMD] − 6.88; 95% CI − 11.27, − 2.49;p = 0.002). Among the different lipid emulsions, fish oil (FO) containing PN reduced the length of intensive care (8 studies; WMD − 3.53; 95% CI − 6.16, − 0.90;p = 0.009) and rate of infectious complications (4 studies; RR 0.65; 95% CI 0.44, 0.95;p = 0.03). When FO was administered as a stand-alone medication outside PN, potential mortality benefits were observed compared to standard care.ConclusionOverall, these findings highlight distinctive omega-6 sparing effects attributed to PN. Among the different lipid emulsions, FO in combination with PN or as a stand-alone treatment may have the greatest clinical impact.Trial registrationPROSPERO international prospective database of systematic reviews (CRD42021259238).Graphical abstract
Genome-wide analysis and functional annotation of chromatin-enriched noncoding RNAs in rice during somatic cell regeneration
Authors: Zhang Yu-Chan , Zhou Yan-Fei , Cheng Yu , Huang Jia-Hui , Lian Jian-Ping , Yang Lu , He Rui-Rui , Lei Meng-Qi , Liu Yu-Wei , Yuan Chao , Zhao Wen-Long , Xiao Shi , Chen Yue-Qin 
Published: January 2022

AbstractBackgroundPlants have the remarkable ability to generate callus, a pluripotent cell mass that acquires competence for subsequent tissue regeneration. Global chromatin remodeling is required for this cell fate transition, but how the process is regulated is not fully understood. Chromatin-enriched noncoding RNAs (cheRNAs) are thought to play important roles in maintaining chromatin state. However, whether cheRNAs participate in somatic cell regeneration in plants has not yet been clarified.ResultsTo uncover the characteristics and functions of cheRNAs during somatic cell reprogramming in plants, we systematically investigate cheRNAs during callus induction, proliferation and regeneration in rice. We identify 2284 cheRNAs, most of which are novel long non-coding RNAs or small nucleolar RNAs. These cheRNAs, which are highly conserved across plant species, shuttle between chromatin and the nucleoplasm during somatic cell regeneration. They positively regulate the expression of neighboring genes via specific RNA motifs, which may interact with DNA motifs around cheRNA loci. Large-scale mutant analysis shows that cheRNAs are associated with plant size and seed morphology. Further detailed functional investigation of two che-lncRNAs demonstrates that their loss of function impairs cell dedifferentiation and plant regeneration, highlighting the functions of cheRNAs in regulating the expression of neighboring genes via specific motifs. These findings supportcis- regulatory roles of cheRNAs in influencing a variety of rice traits.ConclusionscheRNAs are a distinct subclass of regulatory non-coding RNAs that are required for somatic cell regeneration and regulate rice traits. Targeting cheRNAs has great potential for crop trait improvement and breeding in future.
Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy—the MecMeth/NOA-24 trial
Authors: Zeyen Thomas , Potthoff Anna-Laura , Nemeth Robert , Heiland Dieter H. , Burger Michael C. , Steinbach Joachim P. , Hau Peter , Tabatabai Ghazaleh , Glas Martin , Schlegel Uwe , Grauer Oliver , Krex Dietmar , Schnell Oliver , Goldbrunner Roland , Sabel Michael , Thon Niklas , Delev Daniel , Clusmann Hans , Seidel Clemens , Güresir Erdem , Schmid Matthias , Schuss Patrick , Giordano Frank A. , Radbruch Alexander , Becker Albert , Weller Johannes , Schaub Christina , Vatter Hartmut , Schilling Judith , Winkler Frank , Herrlinger Ulrich , Schneider Matthias 
Published: January 2022

Abstract
Background
Glioblastoma is the most frequent and malignant primary brain tumor. Even in the subgroup with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and favorable response to first-line therapy, survival after relapse is short (12 months). Standard therapy for recurrent MGMT-methylated glioblastoma is not standardized and may consist of re-resection, re-irradiation, and chemotherapy with temozolomide (TMZ), lomustine (CCNU), or a combination thereof. Preclinical results show that meclofenamate (MFA), originally developed as a nonsteroidal anti-inflammatory drug (NSAID) and registered in the USA, sensitizes glioblastoma cells to temozolomide-induced toxicity via inhibition of gap junction-mediated intercellular cytosolic traffic and demolishment of tumor microtube (TM)-based network morphology.

Methods
In this study, combined MFA/TMZ therapy will be administered (orally) in patients with first relapse of MGMT-methylated glioblastoma. A phase I component (6–12 patients, 2 dose levels of MFA + standard dose TMZ) evaluates safety and feasibility and determines the dose for the randomized phase II component (2 × 30 patients) with progression-free survival as the primary endpoint.

Discussion
This study is set up to assess toxicity and first indications of efficacy of MFA repurposed in the setting of a very difficult-to-treat recurrent tumor. The trial is a logical next step after the identification of the role of resistance-providing TMs in glioblastoma, and results will be crucial for further trials targeting TMs. In case of favorable results, MFA may constitute the first clinically feasible TM-targeted drug and therefore might bridge the idea of a TM-targeted therapeutic approach from basic insights into clinical reality.

Trial registration
EudraCT 2021-000708-39. Registered on 08 February 2021
Effects of electrode size and placement on comfort and efficiency during low-intensity neuromuscular electrical stimulation of quadriceps, hamstrings and gluteal muscles
Authors: Flodin J. , Juthberg R. , Ackermann P. W. 
Published: January 2022

Abstract
Background
Neuromuscular electrical stimulation (NMES) may prevent muscle atrophy, accelerate rehabilitation and enhance blood circulation. Yet, one major drawback is that patient compliance is impeded by the discomfort experienced. It is well-known that the size and placement of electrodes affect the comfort and effect during high-intensity NMES. However, during low-intensity NMES the effects of electrode size/placement are mostly unknown. Therefore, the purpose of this study was to investigate how electrode size and pragmatic placement affect comfort and effect of low-intensity NMES in the thigh and gluteal muscles.

Methods
On 15 healthy participants, NMES-intensity (mA) was increased until visible muscle contraction, applied with three electrode sizes (2 × 2 cm, 5 × 5 cm, 5 × 9 cm), in three different configurations on quadriceps and hamstrings (short-transverse (ST), long-transverse (LT), longitudinal (L)) and two configurations on gluteus maximus (short-longitudinal (SL) and long-longitudinal (LL)). Current–density (mA/cm2) required for contraction was calculated for each electrode size. Comfort was assessed with a numerical rating scale (NRS, 0–10). Significance was set to p < 0.05 and values were expressed as median (inter-quartile range).

Results
On quadriceps the LT-placement exhibited significantly better comfort and lower current intensity than the ST- and L-placements. On hamstrings the L-placement resulted in the best comfort together with the lowest intensity. On gluteus maximus the LL-placement demonstrated better comfort and required less intensity than SL-placement. On all muscles, the 5 × 5 cm and 5 × 9 cm electrodes were significantly more comfortable and required less current–density for contraction than the 2 × 2 cm electrode.

Conclusion
During low-intensity NMES-treatment, an optimized electrode size and practical placement on each individual muscle of quadriceps, hamstrings and gluteals is crucial for comfort and intensity needed for muscle contraction.
A deep learning model for early risk prediction of heart failure with preserved ejection fraction by DNA methylation profiles combined with clinical features
Authors: Zhao Xuetong , Sui Yang , Ruan Xiuyan , Wang Xinyue , He Kunlun , Dong Wei , Qu Hongzhu , Fang Xiangdong 
Published: January 2022

Abstract
Background
Heart failure with preserved ejection fraction (HFpEF), affected collectively by genetic and environmental factors, is the common subtype of chronic heart failure. Although the available risk assessment methods for HFpEF have achieved some progress, they were based on clinical or genetic features alone. Here, we have developed a deep learning framework, HFmeRisk, using both 5 clinical features and 25 DNA methylation loci to predict the early risk of HFpEF in the Framingham Heart Study Cohort.

Results
The framework incorporates Least Absolute Shrinkage and Selection Operator and Extreme Gradient Boosting-based feature selection, as well as a Factorization-Machine based neural network-based recommender system. Model discrimination and calibration were assessed using the AUC and Hosmer–Lemeshow test. HFmeRisk, including 25 CpGs and 5 clinical features, have achieved the AUC of 0.90 (95% confidence interval 0.88–0.92) and Hosmer–Lemeshow statistic was 6.17 (P = 0.632), which outperformed models with clinical characteristics or DNA methylation levels alone, published chronic heart failure risk prediction models and other benchmark machine learning models. Out of them, the DNA methylation levels of two CpGs were significantly correlated with the paired transcriptome levels (R < −0.3, P < 0.05). Besides, DNA methylation locus in HFmeRisk were associated with intercellular signaling and interaction, amino acid metabolism, transport and activation and the clinical variables were all related with the mechanism of occurrence of HFpEF. Together, these findings give new evidence into the HFmeRisk model.

Conclusion
Our study proposes an early risk assessment framework for HFpEF integrating both clinical and epigenetic features, providing a promising path for clinical decision making.
Managing pregnancy in a spinal muscular atrophy type III patient in Indonesia: a case report
Authors: Setyaningrum Cempaka Thursina Srie , Harahap Indra Sari Kusuma , Nurputra Dian Kesumapramudya , Rachman Irwan Taufiqur , Harahap Nur Imma Fatimah 
Published: January 2022

Abstract
Background
Spinal muscular atrophy is a genetic disorder characterized by degeneration of lower motor neurons, leading to progressive muscular atrophy and even paralysis. Spinal muscular atrophy usually associated with a defect of the survival motor neuron 1 (SMN-1) gene. Classification of spinal muscular atrophy is based on the age of onset and maximum motor function milestone achieved. Although spinal muscular atrophy can be screened for in newborns, and even confirmed earlier genetically, this remains difficult in Third World countries such as Indonesia.

Case presentation
A 28-year-old Asian woman in the first trimester of her second pregnancy, was referred to the neurology department from the obstetric department. Her milestone history showed she was developmentally delayed and the ability to walk independently was reached at 26 months old. At 8 years old, she started to stumble and lose balance while walking. At this age, spinal muscular atrophy was suspected because of her clinical presentations, without any molecular genetic testing. She was married at the age of 25 years and was soon pregnant with her first child. At the gestational age of 32 weeks, her first pregnancy was ended by an emergency caesarean section because of premature rupture of the membranes. In this second pregnancy, she was referred early to the general hospital from the district hospital to receive multidisciplinary care. She and her first daughter underwent genetic testing for spinal muscular atrophy, which has been readily available in our institution since 2018, to confirm the diagnosis and prepare for genetic counseling.

Conclusions
Managing pregnancy in a patient with spinal muscular atrophy should be performed collaboratively. In this case, genetic testing of spinal muscular atrophy and the collaborative management of this patient allowed the clinical decision making and genetic counseling throughout her pregnancy and delivery.