bluuebunny/crossref_metadata_2025 huggingface dataset:
An empirical comparison between polygenic risk scores and machine learning for case/control classification
Authors: Muneeb Muhammad , Feng Samuel , Henschel Andreas
Published: February 2022

BackgroundWe compared the procedure to calculate polygenic risk scores and machine learning for simulated data, devised a way to compare machine learning results with PRS, and highlighted the required files formats for PRS calculation and machine learning model training. For PRS calculation, we used three tools: Plink, PRSice, and Lassosum, and for the machine learning algorithm, we used artificial neural networks. ResultsBased on our survey, we cannot say machine learning is better or polygenic risk scores because it depends on the phenotype under consideration. The average classification AUC of PRSice, Plink, Lassosum, and Machine learning was 0.27, 0.3, 0.35, and 0.87 on simulated data. ConclusionThis article presents the comparison method in an automated way, ultimately assisting in various analyses. For instance, datasets with different heritability or genetic variations can be generated, and the effect on machine learning algorithms' accuracy and PRS's accuracy can be studied. Such analyses may require the generation of multiple datasets, calculation of PRS, and training machine learning model, which can be done quickly using the code segments and scripts provided in this manuscript. Apart from that, we compared the steps of PRS calculation with machine learning and found some steps are optional in machine learning.
Identification of microRNAs associated with heart failure with reduced ejection fraction
Authors: Li Xinli , Zhu Qingqing , Chen Mengli , Cheang Iokfai , Shi Mengsha , Zhang Ting , Gao Rongrong , Yao Wenming
Published: February 2022

Heart failure with reduced ejection fraction (HFrEF) is a complex disease with high mortality. The identification of new biomarkers and regulatory mechanisms for heart failure (HF) remains an important task. The crucial role of miRNAs in regulating the pathophysiological processes of HF has continuously been explored. Notably, the miRNA profiles from cardiac tissue and blood of patients with HFrEF were collected from the Gene Expression Omnibus (GEO) database in this study. After screening the data, two miRNAs (hsa-miR-216a and hsa-miR-217) with the highest cross-validation expression in tissues and blood and one miRNA (hsa-miR-208a) with the highest cross-validation expression in blood were identified. The miRNA-mRNA target gene interaction network and the enrichment analysis of the gene ontology (GO) and Kyoto Encyclopedia of Genomes (KEGG) pathways of differentially expressed miRNAs and target genes showed multiple signaling pathways with specific genes. The consistent expression of miR-217 in myocardial tissue and blood in HFrEF patients and mouse models demonstrates its reliability and repeatability in different etiologies, which will further deepen the understanding of miRNA as a potential biomarker and therapeutic target for heart failure.
The analysis of the impact of bone cement leakage through the endplate on the prognosis of patients after PKP on intervertebral disc
Authors: Qian Zhong-lai , Hua Xi , Lv Nan-ning , Deng Lei , Zhang Jun-Xin
Published: February 2022

Background:There is a high incidence in the elderly who come down with osteoporotic vertebral compression fracture (OVCF) and percutaneous kyphoplasty (PKP) is an effective solution which can relieve pain quickly. Previous studies have shown that both the volume and the distribution of bone cement filling are related to the clinical outcome after PKP surgery. However, the influence of bone cement leakage through the endplate after PKP on intervertebral disc remains to be explained. Methods:118 patients with single level OVCF operated by PKP were retrospectively reviewed from 2015 to 2020. These patients were grouped according to the degree of bone cement leakage. Group A: Bone cement leakage involving one endplate relative to the intervertebral disc. Group B: Bone cement leakage involving one endplate and the adjacent disc. Group C: Bone cement leakage involving both endplates of the intervertebral disc. The following variables were reviewed: gender, age, BMI, BMD and surgical parameters including cement volume (CV), Oswestry Disability Index (ODI), Visual analogue Scale (VAS), Anterior vertebral height ration (AVHR), Local kyphotic angle (LKA), Intervertebral space height (ISH) and the incidence of complications.Results:Compared with the preoperative for all groups, the VAS, ODI, AVHR, LKA and ISH were improved significantly after PKP. There is no significant difference among groups in AVHR and LKA (P> 0.05). Compared with preoperative levels, there was a significant reduction in fracture perivertebral pain in all groups after the surgery, but at the last follow-up, the VAS of Group C were worser than other groups (3.28±0.29 vs. 2.55±0.67vs. 1.73±0.51, P <0.05) and the ODI of Group C were also worser than other groups (44.46±6.65 vs. 35.77±6.33 vs. 29.80±5.96, P <0.05). At the last follow-up, the ISH of group C was worser than group B and group C (4.04±0.38 vs. 4.63±0.27 vs. 5.19±0.34, P <0.05). The complications including the adjacent vertebral fracture (AVF) and backache of group A was (1/39, 2.5%), that of group B was (6/33, 15.4%) and that of group C was (17/22, 42.5%). The incidence of complications in the group C was significantly higher than that in the other groups (P＜0.05). Conclusions:As the area of bone cement leaking from one endplate to another endplate of the intervertebral disc increases, there is no significant difference in the short-term effect after surgery, but the patient's long-term postoperative efficacy becomes worse. The incidence of AVF and back pain of adjacent vertebral bodies increases. It even aggravated the degeneration of the intervertebral disc and the symptoms of discogenic neuralgia appeared.
Treatment with Combined Resveratrol and Myoinositol Ameliorates Endocrine, Metabolic Alterations and Perceived Stress Response in Women with PCOS: A Double-Blind Randomized Clinical Trial
Authors: Hassan Sehresh , Shah Mohsin , Malik Muhammad Omar , Ehtesham Ehtesham , Habib Hamid , Rauf Bushra
Published: February 2022

Purpose: The present study aimed to assess whether treatment with combined resveratrol and myoinositol is more effective in ameliorating the altered parameters associated with PCOS when compared to the combined metformin and pioglitazone therapy.Method: One hundred and ten obese, infertile PCOS women, aged 20-35 years were randomly assigned into two treatment arms. Participants in arm-1 (n=55), received combination of metformin and pioglitazone (1000 mg and 30 mg, respectively), once daily, while those in arm-2 (n=55) received combination of resveratrol and myoinositol (2000 mg and 2000 mg, respectively) once daily for 12 weeks. Evaluations performed at baseline were repeated after 3 months of therapy. The endocrine and metabolic derangements were assessed by measuring serum levels of testosterone, luteinizing hormone, follicle stimulating hormone, adiponectin and insulin using ELISA. Cohen’s perceived stress scale (PSS) was employed as a subjective measure of stress. Results: Pre-treatment PCOS women in both the arms (arm-1 and arm-2) had remarkably elevated serum testosterone and insulin concentrations, low serum adiponectin and high perceived stress response scores. The treatment reduced the altered endocrine indices in arm-2 (resveratrol and myoinositol) participants, manifested by statistically significant reduction in serum testosterone level (p=0.001) and notably increased serum adiponectin level (p=0.001). Interestingly, the hormonal profile, including serum LH and FSH levels also decreased (p<0.001) along with a marked reduction in the ovarian volume (p=0.001) in arm-2 participants. There was a significant reduction in BMI (p<0.001) and an improvement in waist-hip ratio (p<0.001) in arm-2 participants compared to arm-1 group. The PSS scores of the arm-2 subjects improved significantly (p<0.001) whereas, the Ferrimen-gallwey score was improved in both the arms (arm-1 and arm-2; p= 0.010 and 0.008 respectively) however, the change was highly significant in arm-2 (resveratrol and myoinositol). Interestingly, the menstrual regularity was 81.4% in arm-2 while 18.2% in arm-1. We conclude that the therapeutic intervention with combined resveratrol and myoinositol is more effective in ameliorating altered endocrine, metabolic indices and stress burden and could be of clinical importance in high risk group of obese, infertile married PCOS affected women. Trial Registration: Trial registration: ClinicalTials.gov Trial No: NCT04867252. Registered 24 April, 2021, http://clinicaltrials.gov./ct2/show/NCT04867252
Novel RIPK1 Mutations Causing Infantile-onset IBD with Inflammatory and Fistulizing Features
Authors: Sultan Mutaz , Adawi Mohammad , Kol Nitzan , McCourt Blake , Adawi Ihda , Werner Lael , Lev Atar , Snapper Scott , Barel Ortal , Konnikova Liza , Somech Raz , Shouval Dror S.
Published: February 2022

Purpose: Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulator of necroptosis and inflammatory responses. We present the clinical features, genetic analysis and immune work-up of two patients with infantile-onset inflammatory bowel disease (IBD) resulting from novel RIPK1 mutations.Methods: Whole exome and Sanger sequencing was performed in two IBD patients. Mass cytometry time of flight (CyTOF) was conducted for in-depth immunophenotyping on one of the patient’s peripheral blood mononuclear cells, and compared to control subjects and patients with Crohn’s disease.Results: The patients presented with severe colitis and perianal fistulas in the first months of life, without severe/atypical infections. Genetic studies identified novel and pathogenic genetic variants in RIPK1. Using CyTOF unbiased clustering analysis, we identified peripheral immune dysregulation in one of these patients, characterized by an increase in IFNγ CD8+ T cells along with a decrease in monocytes, dendritic cells and B cells. Moreover, RIPK1-deficient patient’s immune cells exhibited decreased IL-6 production in response to LPS across multiple cell types including T cells, B cells and innate immune cells. Summary: Mutations in RIPK1 should be considered in very young patients presenting with colitis and perianal fistulas. Given RIPK1’s role in inflammasome activation, but also in epithelial cells, it is unclear whether IL1 blockade or allogeneic hematopoietic stem cell transplantation can suppress or cure the hyper-inflammatory response in these patients. Additional studies in humans are required to better define the role of RIPK1 in regulating intestinal immune responses, and how treatment can be optimized for patients with RIPK1 deficiency.
Responsible Gambling Through a Motivational Telephone Intervention to High-risk Gamblers – an Evaluation of User Satisfaction and Subjective Intervention Effects
Authors: Håkansson Anders , Franklin Katja , Dahlström Maria , Lyckberg Axel
Published: February 2022

Background: Problem gambling causes major social and psychiatric consequences, and there is need to develop feasible harm-reducing or therapeutic interventions. It has been suggested that gambling operators with responsible gambling intentions can intervene in order to identify and help reduce the harm in problem gamblers. However, user satisfaction, and the risk of negative reactions and gamblers’ transfer to other operators, rarely have been explored scientifically.Methods: This is a retrospective survey study of gamblers reached by a motivational, telephone intervention by the Swedish state-owned gambling operator (Svenska Spel), addressing gamblers with indicators of high-risk gambling practices (n=197). Surveys were answered approximately 10 days after the intervention. Results: Thirty-seven percent perceived their gambling to have decreased due to the intervention, whereas seven percent perceived their gambling instead had increased. A large majority (80 percent) reported a subjective favorable experience from the intervention. Forty percent reported gambling on other operators than Svenska Spel after the intervention, but only seven percent gambled on a new operator following the intervention. Conclusions: Survey data in gamblers reached with a motivational telephone intervention present mainly promising findings, and should be replicated in future studies in larger samples. The main findings display an overwhelmingly favorable subjective experience, and a limited risk of gamblers migrating to other operators.
Associations Among Brain Size and Social-Modulating Hormones with Aggression and Cognitive Performance in a Monogamous Cichlid Fish
Authors: Brandão Manuela Lombardi , de Lima Sheila Pereira , Carvalho Thais Billalba , Gonçalves-de-Freitas Eliane
Published: February 2022

Social behavior is shaped by neural and endocrine mechanisms. In this framework, the social brain hypothesis assumes that bigger brains are selected to cope with complex social environments. On the other hand, hormones can act through organizational and activational effects, modulating brain function during ontogeny and in a fast-changing environment. Here, we test correlations among social-modulating hormones – cortisol, testosterone (T), and 11-ketotestosterone (11KT) – and the volume of specific brain areas with individuals’ social aggression and cognitive abilities in both males and females of the pearl cichlid Geophagus brasiliensis. We observed that, although both parents present similar roles during parental care – biparental brood care – reflecting in similar brain volumes, besides social and cognitive behaviors, the correlation between these factors and hormone levels are different comparing sexes. Females are associated with cortisol, which possibly enhances their cognitive performance, and is linked to bigger telencephalons and diencephalons. Males are influenced by testosterone and its conversion into 11KT, which seems to modulate their behavior. Thus, males’ and females’ social behaviors seem to be evolutionarily driven by similar brains, yet different hormonal activation for coping with the social environment.
Is Land-Applying Biosolids to Agricultural Areas “Sustainable”? Part One: Assessing the Potential Chronic, Sublethal and Lethal Ecotoxicity of Biosolids on Folsomia Candida and Lumbricus Terrestris.
Authors: Puddephatt Karen Joan , McCarthy Lynda Helen , Serre Bryant Micheal
Published: February 2022

The ecotoxicity of biosolids has been studied extensively using single-compound toxicity testing and ‘spiking’ studies; however, little knowledge exists on the ecotoxicity of biosolids as they are land-applied in the Canadian context. The purpose of this study is to elucidate the chronic, sublethal (i.e., behavioural), and lethal impacts of land- applying biosolids on the environmentally-relevant Folsomia candida (springtails) and Lumbricus terrestris (earthworms) and concomitantly ascertain whether the use of biosolids for nutrient amendment is a sustainable practice. This study is part of a larger multi-compartment program which includes terrestrial plants and aquatic arthropods. After an extensive review of government protocols and existing research in the literature, the current study attempted to elucidate the true nature of the potential ecotoxicity of land-applying biosolids, within a laboratory context. Protocols were developed or modified (e.g., using Evans’ boxes (Evans 1947) for chronic and sublethal testing on L. terrestris). Subsequently, two biosolids were tested on springtails and earthworms using avoidance and reproductive bioassay endpoints, at application rates that are standard (8 tonnes ha-1) and worst-case scenarios (22 tonnes ha-1). Results indicated no effect of biosolids at the environmentally-relevant concentration; the worst-case scenario exhibited a positive significantly significant relationship (indicating preference for treatment conditions). We suggest that further assessment of the potential ecotoxicological impact of biosolids employ i) environmentally-relevant organisms, ii) appropriate bioassays including the use of whole-organism endpoints, and iii) multi-kingdom testing (e.g., Kingdom Plantae, Animalia) to comprehensively elucidate answers. Lastly, in situ (field assays) are strongly encouraged in future studies.
Computational Study of the Relative Stability of Some Glass-Ionomer Cement-Forming Molecules
Authors: Gaviria Jair , Quijano Silvia , Quijano Jairo , RUIZ PABLO
Published: February 2022

This work is part of a larger study whose main objective was to find a series of promising molecules to be used as glass-ionomer type materials. The project was divided into 3 successive stages; the results of the first stage have been previously published and were used to continue the study. The molecules evaluated in the second stage were constructed by adding a glycidyl methacrylate molecule to the carboxylic groups of the polyacids selected in the previous stage. The modeling was done using the density functional theory for M06-2X/6-311G(d,p). The results indicate that the addition over the carboxylic groups of the fraction of the molecule corresponding to itaconic acid, is thermodynamically favored. The final stage was modeled with the M06 functional, and consisted of obtaining basic structures of glass-ionomer-type materials, by acid-base reaction between the molecules resulting from the second stage with individual ions of Ca (2+), Zn (2+) or Al (+ 3). It was concluded that aluminum atoms generate more compact structures that would correlate with more resistant materials.
Therapeutic Effects of Triptolide on the Balance of Th17/Treg Cells via AKT/mTOR/p70S6k Signaling Pathway in Lupus-like Mice
Authors: Sun Qice , Liu Yan , Lu Dingqi , Ji Lina , Wang Weijie , Wang Xinchang , Fan Yongsheng , Xie Guanqun
Published: February 2022

T cell subsets play a critical role in immune regulation. T helper 17 (Th17) cells induce tissue inflammation and autoimmune response while regulatory T (Treg) cells mediate autoimmune tolerance and inhibit autoimmune response. Recent studies have shown that the important factors for the pathogenesis and disease activity of systemic lupus erythematosus (SLE), a chronic inflammatory autoimmune disease, are an increased number of Th17 cells and a decreased number or reduced functions of Treg cells. Triptolide is the main active ingredient of Tripterygium wilfordii Hook F (TWHF). It not only has anti-inflammatory, antiproliferative, immune modulation, and proapoptotic activity effects, but is also effective in treating SLE. However, the underlying mechanism of how triptolide works is still unclear. For the purpose of evaluating the impact of triptolide on the induction of Th17 and Treg cells, we conducted relevant experiments with respect to the number and activities of Th17 and Treg cells in vivo and in vitro. In vivo, intragastrically administered triptolide effectively ameliorated the clinical and histological symptoms in lupus-like mice, increased the number of induced Treg cells and reduced the number of Th17 cells in the spleen and their secretion. In vitro, triptolide is able to promote the differentiation of Treg cells and inhibit Th17 formation by inhibiting the AKT/mTOR/p70S6K pathway. Therefore, we posit that triptolide can help to deter the development of inflammation and ultimately treat SLE through regulation of the Th17 and Treg cells balance.
Influence of differences in bone morphology on stress distribution patterns across the trapeziometacarpal joint
Authors: Matsui Yuichiro , Tsukuda Yukinori , Endo Kaori , Matsui Yuki , Kawamura Daisuke , Iwasaki Norimasa
Published: February 2022

We aimed to clarify the effects of morphological patterns of the trapezium and first metacarpal on stress distribution across the articular surface of the trapeziometacarpal (TMC) joint using computed tomography osteoabsorptiometry. Thirty-three patients with normal TMC joints were evaluated. The percentages of the high-density areas in the radial-dorsal and ulnar-volar regions of the trapezium were significantly higher than that in the ulnar-dorsal region, and that of the ulnar-dorsal region of the first metacarpal was significantly lower than in the other three regions. The percentage of the high-density area of the radial-dorsal region of the trapezium and trapezial inclination (TI) showed a significant positive correlation, and the percentages of the high-density areas in the ulnar-dorsal and ulnar-volar regions had significant negative correlations with TI at the articular surface of the first metacarpal. These results indicate that bony morphologic differences in the trapezium affect the stress distribution pattern through the TMC joint.
PT-symmetric distinction of three states and its implementation on a cloud quantum processor
Authors: Balytskyi Yaroslav , Kotukh Yevgen , Khalimov Gennadiy , Chang Sang-Yoon
Published: February 2022

We present a novel $\mathcal{PT}$-symmetric approach for discriminating three pure qubit states and its implementation by the dilation method. Our approach based on the dilation method manipulating the Hilbert space of the system by two-staged $\mathcal{PT}$-symmetric evolution expedites the three-state discrimination process at the cost of introducing an inconclusive outcome. This modification of the Hilbert space of the qubit makes it possible to eliminate one of three states in the limit $\alpha\rightarrow\pm\frac{\pi}{2}$ in the vicinity of the exceptional point corresponding to coalescing eigenvectors and eigenvalues, effectively reducing the problem to two-state discrimination, or reducing the geometry to the mirror-symmetric states for which an efficient discrimination strategy is developed. To demonstrate the effectiveness of our approach, we implement it on a superconducting quantum processor provided by IBM Quantum Experience employing an ancilla qubit. We conclude our paper by identifying potential applications, including those in quantum communication and cryptography, to facilitate further research and development.
Initial experience of a deep learning application for the differentiation of Kikuchi-Fujimoto’s disease from tuberculous lymphadenitis on neck CECT
Authors: Kim Byung Hun , Lee Changhwan , Lee Ji Young , Tae Kyung
Published: February 2022

Neck contrast-enhanced CT (CECT) is a routine tool used to evaluate patients with cervical lymphadenopathy. This study aimed to evaluate the ability of convolutional neural networks (CNNs) to classify Kikuchi-Fujimoto’s disease (KD) and cervical tuberculous lymphadenitis (CTL) on neck CECT in patients with benign cervical lymphadenopathy. A retrospective analysis of consecutive patients with biopsy-confirmed KD and CTL in a single center, from January 2012 to June 2020 was performed. This study included 198 patients of whom 125 patients (mean age, 25.1 years ± 8.7, 31 men) had KD and 73 patients (mean age, 41.0 years ± 16.8, 34 men) had CTL. A neuroradiologist manually labelled the enlarged lymph nodes on the CECT images. Using these labels as the reference standard, a CNN was developed to classify the findings as KD or CTL. The CT images were divided into training (70%), validation (10%), and test (20%) subsets. The Cut&Remain method was applied to improve performance. For the test set, the best area under the receiver operating characteristic curve for classifying KD from CTL was 0.91. Our findings show that the differentiation of KD from CTL on neck CECT using a CNN is feasible with high diagnostic performance.
A Hybrid Method Based on Semi-Supervised Learning for Relation Extraction in Chinese EMRs
Authors: Yang Chunming , Xiao Dan , Luo Yuanyuan , Li Bo , Zhao Xujian , Zhang Hui
Published: February 2022

Background: Building a large-scale medical knowledge graphs needs to automatically extract the relations between entities from electronic medical records(EMRs) . The main challenges are the scarcity of available labeled corpus and the identification of complexity semantic relations in text of Chinese EMRs. A hybrid method based on semi-supervised learning is proposed to extract the medical entity relations from small-scale complex Chinese EMRs. Methods: The semantic features of sentences are extracted by a residual network(ResNet) and the long dependent information is captured by bidirectional GRU(Gated Recurrent Unit). Then the attention mechanism is used to assign weights for the extracted features respectively, and the output of two attention mechanisms is integrated for relation prediction. We adjusted the training process with manually annotated small-scale relational corpus and bootstrapping semi-supervised learning algorithm, and continuously expanded the datasets during the training process. Results: We constructed a small corpus of Chinese EMRs relation extraction based on the EMR datasets released at the CCKS(China Conference on Knowledge Graph and Semantic Computing). The experimental results show that the best F1-score of the proposed method on the overall relation categories reaches 89.78%, which is 13.07% higher than the baseline CNN.
CLUSTER: A biomarker-integrated targeted therapy study in patients with advanced non-small cell lung cancer
Authors: Zhou Qing , Chen Hua-Jun , Wang Bin-Chao , Wang Zhen , Tu Hai-Yan , Xu Chongrui , Zheng Ming-Ying , Bai Xiao-Yan , Sun Yue-Li , Yan Hong-hong , Gan Bin , Tao Hong , Wang Yingying , Zhao Sylvia , Yang Jin-Ji , Lai Clinton , Wu Yi-Long
Published: February 2022

The CLUSTER umbrella trial simultaneously investigated the efficacy of multiple targeted therapies in Chinese patients with advanced non-small cell lung cancer and pre-specified genetic alterations. Patients were assigned to receive capmatinib (METi), ceritinib (ALKi), binimetinib (MEKi), or alpelisib (PI3Kαi) matched to their genetic alteration. The overall response rate (ORR) and safety of each treatment were determined. Ceritinib met the pre‑specified statistical threshold for efficacy with an ORR of 73%, whereas an ORR of 19% and 9% were attained with capmatinib and binimetinib, respectively. Although not a predefined endpoint, a post-hoc analysis of the overall anti-tumor activity in all treated patients showed encouraging results. Despite the limited number of patients in some of the treatment arms and the stringent criteria for preliminary activity, these findings confirm the feasibility of conducting biomarker-integrated studies in China, and warrant the implementation of further umbrella trials to simultaneously evaluate the efficacy of multiple targeted treatments. Trial registration number: NCT02276027
A Novel Tumor Suppressor Gene, TMEM171, Inhibits the Development of Gastric Cancer by Dephosphorylating IKBα and Inactivating the NF-kB Signaling Pathway
Authors: Li De-feng , Tang Qi , Yang Mei-feng , Bing Yu-ling , Peng Quan-zhou , Wang Li-sheng , Yao Jun
Published: February 2022

Background: Gastric cancer (GC) is one of the most common malignant tumors with an unsatisfactory prognosis worldwide. Therefore, it is urgently necessary to explore the mechanism underlying the tumorigenesis of GC. Methods: In the present study, we identified that TMEM171 was down-regulated in GC tissues, and its expression was closely associated with the prognosis of GC patients based on the data from Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). Subsequently, qRT-PCR, Western blotting analysis, and immunohistochemistry (IHC) assay were performed to detect the expression of TMEM171 in GC tissues and cell lines. The functional roles and underlying mechanisms of TMEM171 involved in GC growth were also explored in vitro and in vivo.Results: TMEM171 was remarkably down-regulated in GC tissues and GC cell lines. Functionally, overexpression of TMEM171 suppressed the proliferation of GC cells and promoted the apoptosis of GC cells, whereas depletion of TMEM171 contributed to the opposite trend in vitro and in vivo. TMEM171 functioned as an inhibitor for GC proliferation through dephosphorylating IκBα and then inactivating the canonical NF-κB signaling pathway. Conclusions: This study revealed the vital role of TMEM171 in GC, highlighting the regulatory function of the TMEM171/IκBα/NF-κB signaling pathway in modulating GC progression. Collectively, our findings provided a novel prognostic and therapeutic target for GC patients.
Two distinct kinases responsible for the phosphorylation of tyrosine residues of Gab2 in neutrophil precursor cell upon G-CSF stimulation.
Authors: Miyoshi Mana , Kawano Shun-ichiro , Zhao Xianglin , Ide Toru , Murakami Hiroshi
Published: February 2022

Gab2 is one of the most heavily tyrosine-phosphorylated protein in granulocyte precursor cell, GM-I62-1, upon G-CSF stimulation. Effects of several pharmacological inhibitors to tyrosine kinases were examined on the tyrosine phosphorylation of Gab2 upon G-CSF stimulation. Specific Src kinase inhibitor, PP1, had marginal effects, if any, on the Gab2 tyrosine phosphorylation. In contrast, Syk specific inhibitors, Piceatannol and GS-9973, had partial but distinct inhibitory effects on the Gab2 tyrosine phosphorylation upon G-CSF stimulation. When the tyrosine residues are phosphorylated, downstream effector molecules, SHP2 and p85 subunit of PI3K, are known to bind to these phosphorylated residues of Gab2 through their SH2 domains. Pretreatments of cells with Syk specific inhibitors reduced the SHP2 binding to Gab2. However, no inhibitory effect of these inhibitors on p85 binding to Gab2 was observed. These observations indicated that Syk phosphorylates tyrosine residues of SHP2 binding sites of Gab2, and that the tyrosine residues of Gab2 to which p85 subunit of PI3K binds upon G-CSF stimulation are phosphorylated by other tyrosine kinase(s).
17β-Estradiol (E2) Alleviates Depressive-Like Behaviors By Inhibiting Gp130/JAK1/STAT3 Signaling Pathway Through Estrogen Receptor-β
Authors: Chen Qian , Sun Ting , Cheng Jingru , Mei Yufeng , Liu Bohao , Li Yan
Published: February 2022

Background: Neuroinflammation has an important role in the pathogenesis of depression, and estrogen can inhibit the secretion of inflammatory factors IL-6 and TNF-and relieve depression-like behaviors in MDD patients. The gp130 / JAK1 / STAT3-mediated neuroinflammation plays an important role in the pathogenesis of depression. Exploring the specific mechanism of estrogen inhibition of neuroinflammation in depression has a positive effect on the treatment of MDD.Methods: Wild-type female C57BL / 6 mice were randomly divided into control mice, OVX mice and OVX + E2 mice, and OVX + E2 mice were pretreated with a 0.2 mg/kg/day dose for one month to observe their depression-like behavior. In addition, E2 was also used to interfere with the BV2 cells. Intraperitoneal injection of E2 after OVX confirmed the therapeutic effect of E2 and further verified the molecular mechanism of E2.Results: the inflammatory response and impairment was significantly reduced and the depression-like behavior was alleviated in OVX+E2 group. Moreover, gp130 / JAK1 / STAT3 signaling pathway was also downregulated. On the other hand, hippocampal apoptosis was significantly reduced in mice in the OVX + E2 group. We further demonstrated that E2 inhibited gp130 / JAK1 / STAT3 signaling pathway via estrogen receptor-β (ER-β).Conclusion: we confirmed the anti-depressant effect and anti-apoptotic of E2 we verified that E2 alleviated inflammatory response and depressive-like behaviors by inhibiting gp130/JAK1/STAT3 signaling pathway via combining with ER-β and gp130. This study suggested that E2 exerted neuroprotective effects and estrogen replacement therapy will be a promising therapeutic strategy to alleviate neuroinflammation and depressive-like behaviors.
First Clinical Experience With [89Zr]Zr-Df-IAB22M2C PET/MRI in Patients With Metastatic Cancer
Authors: Schwenck Johannes , Sonanini Dominik , Seyfried Dominik , Ehrlichmann Walter , Kienzle Gabriele , Reischl Gerald , Krezer Pascal , Wilson Ian , Korn Ron , Gonzalez-Menendez Irene , Quintanilla-Martinez Leticia , Seith Ferdinand , Forschner Andrea , Eigentler Thomas , Zender Lars , Röcken Martin , Pichler Bernd , Flatz Lukas , Kneilling Manfred , Fougère Christian la
Published: February 2022

Aim/Introduction: Despite the spectacular success of immune checkpoint inhibitor therapy (ICT) in patients with metastatic cancer, only a limited proportion of patients benefit from ICT. An important gatekeeper for the therapeutic response to ICT are CD8+ cytotoxic T cells which are able to recognize MHC class I-dependent tumor antigens and destroy tumor cells. The radiolabeled minibody [89Zr]Zr-Df-IAB22M2C has a high affinity for human CD8+ T cells and was already successfully tested in a phase I study. Here, we aimed to gain first clinical PET/MRI experience with the non-invasive assessment of the CD8+ T cell distribution in cancer patients by in vivo [89Zr]Zr-Df-IAB22M2C.Material and Methods: We investigated 8 patients with metastasized cancers undergoing ICT. Radiolabeling of Df-IAB22M2C with Zr-89 was performed according to Good Manufacturing Practice. Multiparametric PET/MRI was acquired 24 h after injection of 74.2±17.9 MBq [89Zr]Zr-Df-IAB22M2C. We analyzed the [89Zr]Zr-Df-IAB22M2C uptake within the metastases and primary and secondary lymphatic organs. Results: [89Zr]Zr-Df-IAB22M2C injection was tolerated well without noticeable side effects. The CD8 PET/MRI data acquisitions 24 hours post administration of [89Zr]Zr-Df-IAB22M2C revealed a good image quality with a relatively low background signal due to only low unspecific tissue uptake and marginal blood pool retention. Only two metastatic lesions showed a markedly increased tracer uptake in our cohort of patients. Furthermore, we observed a high interpatient variability in the [89Zr]Zr-Df-IAB22M2C uptake within the primary and secondary lymphoid organs. Four out of five ICT patients exhibited a rather high [89Zr]Zr-Df-IAB22M2C uptake in the bone marrow. Two of these four patients as well as two other patients yielded a pronounced [89Zr]Zr-Df-IAB22M2C uptake within non metastatic lymph nodes. Interestingly, cancer progression in ICT patients was associated with a relatively low [89Zr]Zr-Df-IAB22M2C uptake in the spleen compared to the liver in 4 out of the 6 patients.Conclusion: Our first clinical experiences revealed the feasibility of [89Zr]Zr-Df-IAB22M2C PET/MRI to assess potential immune-related changes in the metastases and the primary and secondary lymphatic organs. According to our results, we hypothesize that alteration in the [89Zr]Zr-Df-IAB22M2C uptake in primary and secondary lymphoid organs might be associated with the response to ICT.
Inspiratory Hyperoxia Suppresses Lung Cancer Metastasis Through A MYC/SLC1A5-Dependent Metabolic Pathway
Authors: Liu Xiucheng , Qin Hao , Feng Shoujie , Zhuang Wei , Quan Xiaoyu , Lv Yin , Guo Chen , Chen Chang , Zhang Hao
Published: February 2022

Background The lack of knowledge about the effect of inspiratory hyperoxia (IH) on the lung-specific tumor microenvironment and progression of lung cancer has attracted considerable attention.Methods The effects of different oxygenation parameters on the proliferation, apoptosis, invasion and migration of lung cancer cells were systematically evaluated in vitro and in vivo, including CCK-8, transwell and metastasis models. Mechanistically, transcriptome, proteome and metabolome analysis were combined to reveal the effects of IH on the malignant phenotype of lung cancer cell. Luciferase reporter analysis, Western blot, RNA immunoprecipitation and immunohistochemical staining were performed to examine the detailed regulatory mechanism of IH regulating metabolic reprogramming of lung cancer cells.Results Our results reveal that IH treatment (60% O2, 6h/day) not only has no tumor progression-promoting effects, but also suppresses lung cancer metastasis and promotes long-term survival. MYC/SLC1A5-induced metabolic reprogramming and glutamine addiction serves as a new mechanism that drives lung cancer metastasis, which can be significantly suppressed by IH.Conclusion MYC/SLC1A5-induced metabolic reprogramming and glutamine addiction is a new mechanism that drives lung cancer metastasis, which can be significantly suppressed by IH treatment. These findings are relevant to the debate on the perils, promises and antitumor effect of IH, especially for patients with lung cancer.
Quantification of Acceleration as Activity Counts in ActiGraph Wearables
Authors: Neishabouri Ali , Nguyen Joe , Samuelsson John , Guthrie Tyler , Biggs Matt , Wyatt Jeremy , Cross Doug , Karas Marta , Migueles Jairo Hidalgo , Khan Sheraz , Guo Christine Cong
Published: February 2022

Background

Digital clinical measures based on data collected by wearable devices have seen rapid growth in both clinical trials and healthcare. The widely-used measures based on wearables are epoch-based physical activity counts using accelerometer data. Even though activity counts have been the backbone of thousands of clinical and epidemiological studies, there are large variations of the algorithms that compute counts and their associated parameters – many of which have often been kept proprietary by device providers. This lack of transparency has hindered comparability between studies using different devices and limited their broader clinical applicability. ActiGraph devices have been the most-used wearable accelerometer devices for over two decades.

Results

Recognizing the importance of data transparency, interpretability and interoperability to both research and clinical use, we here describe the detailed counts algorithms of five generations of ActiGraph devices going back to the first AM7164 model, and publish the current counts algorithm in ActiGraph’s ActiLife and CentrePoint software as a standalone Python package for research use.

Conclusion

We believe that this material will provide a useful resource for the research community, accelerate digital health science and facilitate clinical applications of wearable accelerometry.
Computer Vision Reveals Fish Behaviour Through Structural Equation Modelling of Movement Patterns
Authors: Lopez-Marcano Sebastian , Turschwell Mischa P , Brown Christopher J , Jinks Eric L , Wang Dadong , Connolly Rod M
Published: February 2022

Background: Studying and quantifying fish behaviour is important to understand how fish interact with their environments. Yet much of fish behaviour in aquatic ecosystems remains hard to observe and time-consuming to manually document. Automated tracking through computer vision techniques can provide fine-scale movement data of many individuals across spatial and temporal scales. When used alongside statistical methodologies such as structural equation models (SEMs), these data can be used to infer underlying latent behavioural events of an animal without direct observations. However, interpreting the main modes of fish behaviour when presented with large datasets remains a challenge. Methods: We developed a cross-validation routine to evaluate methods for accurately predicting behaviour from a large field dataset. We created SEM behavioural models using different combinations of temporal buffers in training data and evaluated them against a fixed evaluation dataset for three common fish species (Moses perch, southern herring and yellowfin bream). We then used the SEM model with the lowest error for each species to translate movement data into ecologically relevant behavioural events. Results: The temporal buffer generating the SEM models with the best predictive capacity varied among species, from 1 min for Moses perch and southern herring, to 45 min for yellowfin bream. Models were able to accurately predict behavioural events such as foraging (slow, sinuous movement near the substrate) and fine-scale diurnal migration (fast, directional movement near the surface).Conclusions: We developed a framework to optimise temporal partitioning in computer vision tracking data using SEMs. We demonstrate how data can be translated into ecologically relevant behavioural events such as foraging and fine-scale migrations. This is a step towards bridging the gap between development and application of new technologies to monitor behaviour of animals in aquatic ecosystems.
Dosimetric comparison of AcurosBV with AAPM TG43 dose calculation formalism in cervical intraductal high-dose-rate brachytherapy using three different applicators
Authors: Dai Zhitao , Bi Su-yan , Chen Zhi-jian , Sun Xing-ru
Published: February 2022

Purpose: To compare the dosimetric effects of American Association of Physicists in Medicine (AAPM) TG43 dose formalism and AcurosBV ( grid-based Boltzmann solver ,GBBS) formalism on High-dose-rate(HDR) brachytherapy planning for cervical cancer patients irradiated using three different applicators.Methods: A TG43 plan and a AcurosBV plan were generated for each of the 30 patients. twenty patients who had undergone whole pelvic radiotherapy followed by cervical HDR brachytherapy and the remaining 10 patients who underwent total hysterectomy only gave HDR brachytherapy also were enrolled in this study. The patients were divided into three groups according to the types of applicators used: tandem and ovoid (T&O), tandem and ring (T&R), and Cylinder. To compare the dosimetric parameters, the cumulative dose-volume histograms (DVHs) were measured. We also compared the doses at 90% of the volume (D90%) , the volume receiving 100% and 150% of the prescribed dose (V100% and V150%) for the clinical target volume (CTV-HR) and the doses of point A, the dose receiving 0.1 cc and 2 cc of the volume (D0.1cc and D2cc) for the organs-at-risk (OARs).Results: In this study, compared with the AcurosBV plans, TG43 plans predicted higher D90%, V100%, and V150% of CTV-HR, dose of point A and D0.1cc and D2cc of OARs in three types of applicators. Except D2cc of sigmoid in T&R and Cylinder applicators, the D90%, V100%, and V150% of CTV-HR; the Dose of point A and the D0.1cc and D2cc of bladder, recutum and small bowel exhibited significant discrepancies (P>0.05). The effects of the three types of applicators on the dose distribution were quite different due to the difference of the materials: The dose difference of CTV-HR and OARs was greatest (around 10%) for T&O applicators but only 1%-5% for T&R and Cylinder applicators.Conclusions: This study demonstrated that AcurosBV was more accurate in calculating the doses in the air cavity and high-density substance than TG43. In the clinical setting, the AcurosBV exhibited different dosimetric distributions in the cervix plans for HDR brachytherapy, especially in treatment planning when using T&O applicators. The AcurosBV algorithm should be considered when using T&O applicators or some other materials with a much higher or lower density (metal or air) than soft tissue. Howevere, If the density is close to the soft tissue, considering AcurosBV algorithm requires more calculation time, TG43 could still be selected when using applicators in clinical.
High CENPA expression in papillary renal cell carcinoma tissues is associated with poor prognosis
Authors: li Junwu , Li Qinke , Xie Yiteng , Zhang Yuanfeng , Zhang Ronggui
Published: February 2022

Objective: This work focused on investigating the relation of centromeric protein A (CENPA) gene expression with prognosis of papillary renal cell carcinoma (PRCC). Methods: We obtained data from PRCC cases in TCGA. Thereafter, CENPA levels between the paired PRCC and matched non-carcinoma samples were analyzed by Wilcoxon rank-and-sum test, while the relations of clinicopathological characteristics with CENPA level were examined by logistic regression and Wilcoxon rank-sum test. The prognostic value of CENPA was assessed by plotting the receiver operating feature curve (ROC) and calculating the value of area under curve (AUC). In addition, relations between clinicopathological features and PRCC survival were analyzed through Kaplan-Meier (KM) and Cox regression analyses. Additionally, we constructed a nomogram according to multivariate Cox regression results for predicting how CENPA affected patient survival. We also determined CENPA levels within cancer and matched non-carcinoma samples through immunohistochemistry (IHC). Finally, we utilized functional enrichment for identifying key pathways related to differentially expressed genes (DEGs) between PRCC cases with CENPA up-regulation and down-regulation. Results: CENPA expression enhanced in PRCC tissues compared with healthy counterparts (P <0.001). CENPA up-regulation was related to clinical stage and pathological TNM stage (P<0.05). Meanwhile, the ROC curve indicated that CENPA had a remarkable diagnostic capacity for PRCC (AUC=0.936). As revealed by KM curve, PRCC cases with CENPA up-regulation were associated with poor survival compared with those with CENPA down-regulation (risk ratio, RR=3.07, 95% CI: 1.58-5.97, P=0.001). In the meantime, univariate as well as multivariate analysis showed an independent association of CENPA with overall survival (OS, P <0.001). IHC analysis indicated that PRCC cases showed an increased CENPA positive rate compared with controls. As revealed by functional annotations, CENPA was enriched into pathways associated with KEGG - NEUROACTIVE - LIGAND - RECEPTOR - INTERACTION, KEGG - CYTOKINE - CYTOKINE - RECEPTOR INTERACTION, NABA - ECM - REGULATORS, NABA - ECM - GLYCOPROTEINS, and NABA - CORE - MATRISOME pathways. Conclusion: CENPA expression increases within PRCC samples, which predicts dismal PRCC survival. CENPA may become a molecular prognostic marker and therapeutic target for PRCC patients.
Evaluation of Quality of Neonatal Intensive Care Unit Service in Primary Hospitals of Jimma Zone, Southwest Ethiopia
Authors: Fikadu Lamesa , Adamu Kidist , Haile Yosef
Published: February 2022

Background: Neonatal Intensive Care Unit (NICU) is a health facility based package of interventions to address newborns that need advanced care for ill or premature new-borns in the first 28 days of life. The period with in the first month of life was the most important time for child’s survival and they face the highest risk of death. There is paucity of information regarding this important issue in south west Ethiopia therefore, it is very important to evaluate quality of neonatal Intensive Care Unit services especially in the era of mid covid-19 pandemic. Hence, the aim of this study was to evaluate the quality of neonatal intensive care unit service at primary hospitals in Jimma zone, 2020. Methods: A single case study using both quantitative and qualitative data collection methods was conducted from August 20 to September 15, 2020 in neonatal intensive care units of primary hospitals located in Jimma zone. The evaluation was done using Donabedian’s Structure-Process-Outcome model in terms of availability, compliance and acceptability dimensions. Data were entered in EpiData version 3.1 and analyzed using SPSS version 25. Descriptive statistics was used to summarize the data. Bivariate and multivariable logistic regression analyses were performed to see the association between independent variable and satisfaction of parents on quality of service. The quantitative findings were supplemented with qualitative data. Finally the findings of the evaluation were interpreted on the basis of pre-determined judgment matrix.Results: Most of the required resources (88.32%) were available at the study sites. But the rooms had been inadequate. Health care providers’ compliance was 82.59%. However, after discharge, only 26.67% of neonates received appointment based on guideline. About 72.75% of parents were satisfied with the services given to their babies. The overall quality of neonatal intensive care service was partially implemented (82.42%) according to the preset judgment criteria. Parental satisfaction was found to be associated with place of residence (AOR=3.68, 95 % CI: 1.15-11.76) and occupation (AOR=2.69, 95% CI: 1.01-7.2).Conclusions and Recommendations: The overall quality of neonatal intensive care service was partially implemented according to the preset judgment criteria. Rural residence and having no occupation were predictors for parenteral satisfaction. There is a need for improvements on preparation of maternal waiting area, hand washing facilities, provision of appointments to discharged neonates and the availability of medical equipment’s (Continuous Positive Airway Pressure).