bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors
Authors: Li Yangyang , Zhang Yu , Cao Guoshuai , Zheng Xiaodong , Sun Cheng , Wei Haiming , Tian Zhigang , Xiao Weihua , Sun Rui , Sun Haoyu 
Published: June 2021

Abstract
Background
Although checkpoint-based immunotherapy has shown exciting results in the treatment of tumors, around 70% of patients have experienced unresponsiveness. PVRIG is a recently identified immune checkpoint receptor and blockade of which could reverse T cell exhaustion to treat murine tumor; however, its therapeutic potential via NK cells in mice and human remains seldom reported.

Methods
In this study, we used patient paraffin-embedded colon adenocarcinoma sections, various murine tumor models (MC38 colon cancer, MCA205 fibrosarcoma and LLC lung cancer), and human NK cell- or PBMC-reconstituted xenograft models (SW620 colon cancer) to investigate the effect of PVRIG on tumor progression.

Results
We found that PVRIG was highly expressed on tumor-infiltrating NK cells with exhausted phenotype. Furthermore, either PVRIG deficiency, early blockade or late blockade of PVRIG slowed tumor growth and prolonged survival of tumor-bearing mice by inhibiting exhaustion of NK cells as well as CD8+ T cells. Combined blockade of PVRIG and PD-L1 showed better effect in controlling tumor growth than using either one alone. Depletion of NK or/and CD8+ T cells in vivo showed that both cell types contributed to the anti-tumor efficacy of PVRIG blockade. By using Rag1−/− mice, we demonstrated that PVRIG blockade could provide therapeutic effect in the absence of adaptive immunity. Further, blockade of human PVRIG with monoclonal antibody enhanced human NK cell function and inhibited human tumor growth in NK cell- or PBMC-reconstituted xenograft mice.

Conclusions
Our results reveal the importance of NK cells and provide novel knowledge for clinical application of PVRIG-targeted drugs in future.
Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib
Authors: Fujii Yasutoshi , Ono Atsushi , Hayes C. Nelson , Aikata Hiroshi , Yamauchi Masami , Uchikawa Shinsuke , Kodama Kenichiro , Teraoka Yuji , Fujino Hatsue , Nakahara Takashi , Murakami Eisuke , Miki Daiki , Okamoto Wataru , Kawaoka Tomokazu , Tsuge Masataka , Imamura Michio , Chayama Kazuaki 
Published: June 2021

AbstractBackgroundThere has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN).MethodWe retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated.ResultsIn total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes wereTP53(54%),CTNNB1(42%),TERT(42%),ATM(25%), andARID1A(13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmeanfor predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed.ConclusionOur study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.
Long non-coding RNA DLEU2 drives EMT and glycolysis in endometrial cancer through HK2 by competitively binding with miR-455 and by modulating the EZH2/miR-181a pathway
Authors: Dong Peixin , Xiong Ying , Konno Yosuke , Ihira Kei , Kobayashi Noriko , Yue Junming , Watari Hidemichi 
Published: June 2021

Abstract
Background
Epithelial-to-mesenchymal transition (EMT) and aerobic glycolysis are fundamental processes implicated in cancer metastasis. Although increasing evidence demonstrates an association between EMT induction and enhanced aerobic glycolysis in human cancer, the mechanisms linking these two conditions in endometrial cancer (EC) cells remain poorly defined.

Methods
We characterized the role and molecular mechanism of the glycolytic enzyme hexokinase 2 (HK2) in mediating EMT and glycolysis and investigated how long noncoding RNA DLEU2 contributes to the stimulation of EMT and glycolysis via upregulation of HK2 expression.

Results
HK2 was highly expressed in EC tissues, and its expression was associated with poor overall survival. Overexpression of HK2 effectively promoted EMT phenotypes and enhanced aerobic glycolysis in EC cells via activating FAK and its downstream ERK1/2 signaling. Moreover, microRNA-455 (miR-455) served as a tumor suppressor by directly interacting with HK2 mRNA and inhibiting its expression. Furthermore, DLEU2 displayed a significantly higher expression in EC tissues, and increased DLEU2 expression was correlated with worse overall survival. DLEU2 acted as an upstream activator for HK2-induced EMT and glycolysis in EC cells through two distinct mechanisms: (i) DLEU2 induced HK2 expression by competitively binding with miR-455, and (ii) DLEU2 also interacted with EZH2 to silence a direct inhibitor of HK2, miR-181a.

Conclusions
This study identified DLEU2 as an upstream activator of HK2-driven EMT and glycolysis in EC cells and provided significant mechanistic insights for the potential treatment of EC.
Breast cancer risk factors in relation to molecular subtypes in breast cancer patients from Kenya
Authors: Sayed Shahin , Fan Shaoqi , Moloo Zahir , Wasike Ronald , Bird Peter , Saleh Mansoor , Shaikh Asim Jamal , Figueroa Jonine D. , Naidoo Richard , Makokha Francis W. , Gardner Kevin , Oigara Raymond , Njoroge Faith Wambui , Magangane Pumza , Mutebi Miriam , Chauhan Rajendra , Mwanzi Sitna , Govender Dhirendra , Yang Xiaohong R. 
Published: June 2021

Abstract
Background
Few studies have investigated risk factor heterogeneity by molecular subtypes in indigenous African populations where prevalence of traditional breast cancer (BC) risk factors, genetic background, and environmental exposures show marked differences compared to European ancestry populations.

Methods
We conducted a case-only analysis of 838 pathologically confirmed BC cases recruited from 5 groups of public, faith-based, and private institutions across Kenya between March 2012 to May 2015. Centralized pathology review and immunohistochemistry (IHC) for key markers (ER, PR, HER2, EGFR, CK5-6, and Ki67) was performed to define subtypes. Risk factor data was collected at time of diagnosis through a questionnaire. Multivariable polytomous logistic regression models were used to determine associations between BC risk factors and tumor molecular subtypes, adjusted for clinical characteristics and risk factors.

Results
The median age at menarche and first pregnancy were 14 and 21 years, median number of children was 3, and breastfeeding duration was 62 months per child. Distribution of molecular subtypes for luminal A, luminal B, HER2-enriched, and triple negative (TN) breast cancers was 34.8%, 35.8%, 10.7%, and 18.6%, respectively. After adjusting for covariates, compared to patients with ER-positive tumors, ER-negative patients were more likely to have higher parity (OR = 2.03, 95% CI = (1.11, 3.72), p = 0.021, comparing ≥ 5 to ≤ 2 children). Compared to patients with luminal A tumors, luminal B patients were more likely to have lower parity (OR = 0.45, 95% CI = 0.23, 0.87, p = 0.018, comparing ≥ 5 to ≤ 2 children); HER2-enriched patients were less likely to be obese (OR = 0.36, 95% CI = 0.16, 0.81, p = 0.013) or older age at menopause (OR = 0.38, 95% CI = 0.15, 0.997, p = 0.049). Body mass index (BMI), either overall or by menopausal status, did not vary significantly by ER status. Overall, cumulative or average breastfeeding duration did not vary significantly across subtypes.

Conclusions
In Kenya, we found associations between parity-related risk factors and ER status consistent with observations in European ancestry populations, but differing associations with BMI and breastfeeding. Inclusion of diverse populations in cancer etiology studies is needed to develop population and subtype-specific risk prediction/prevention strategies.
Serum metabolomics in chickens infected with Cryptosporidium baileyi
Authors: Wu Xue-Mei , Yang Xin , Fan Xian-Cheng , Chen Xi , Wang Yu-Xin , Zhang Long-Xian , Song Jun-Ke , Zhao Guang-Hui 
Published: June 2021

Abstract
Background
Cryptosporidium baileyi is an economically important zoonotic pathogen that causes serious respiratory symptoms in chickens for which no effective control measures are currently available. An accumulating body of evidence indicates the potential and usefulness of metabolomics to further our understanding of the interaction between pathogens and hosts, and to search for new diagnostic or pharmacological biomarkers of complex microorganisms. The aim of this study was to identify the impact of C. baileyi infection on the serum metabolism of chickens and to assess several metabolites as potential diagnostic biomarkers for C. baileyi infection.

Methods
Ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) and subsequent multivariate statistical analysis were applied to investigate metabolomics profiles in the serum samples of chickens infected with C. baileyi, and to identify potential metabolites that can be used to distinguish chickens infected with C. baileyi from non-infected birds.

Results
Multivariate statistical analysis identified 138 differential serum metabolites between mock- and C. baileyi-infected chickens at 5 days post-infection (dpi), including 115 upregulated and 23 downregulated compounds. These metabolites were significantly enriched into six pathways, of which two pathways associated with energy and lipid metabolism, namely glycerophospholipid metabolism and sphingolipid metabolism, respectively, were the most enriched. Interestingly, some important immune-related pathways were also significantly enriched, including the intestinal immune network for IgA production, autophagy and cellular senescence. Nine potential C. baileyi-responsive metabolites were identified, including choline, sirolimus, all-trans retinoic acid, PC(14:0/22:1(13Z)), PC(15:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)), PE(16:1(9Z)/24:1(15Z)), phosphocholine, SM(d18:0/16:1(9Z)(OH)) and sphinganine.

Conclusions
This is the first report on serum metabolic profiling of chickens with early-stage C. baileyi infection. The results provide novel insights into the pathophysiological mechanisms of C. baileyi in chickens.

Graphic abstract
Amaryllidaceae plants: a potential natural resource for the treatment of Chagas disease
Authors: Martínez-Peinado Nieves , Cortes-Serra Nuria , Tallini Luciana R. , Pinazo Maria-Jesus , Gascon Joaquim , Bastida Jaume , Alonso-Padilla Julio 
Published: June 2021

Abstract
Background
Chagas disease is a neglected zoonosis caused by the parasite Trypanosoma cruzi. It affects over six million people, mostly in Latin America. Drugs available to treat T. cruzi infection have associated toxicity and questionable efficacy at the chronic stage. Hence, the discovery of more effective and safer drugs is an unmet medical need. For this, natural products represent a pool of unique chemical diversity that can serve as excellent templates for the synthesis of active molecules.

Methods
A collection of 79 extracts of Amaryllidaceae plants were screened against T. cruzi. Active extracts against the parasite were progressed through two cell toxicity assays based on Vero and HepG2 cells to determine their selectivity profile and discard those toxic to host cells. Anti-T. cruzi-specific extracts were further qualified by an anti-amastigote stage assay.

Results
Two extracts, respectively from Crinum erubescens and Rhodophiala andicola, were identified as highly active and specific against T. cruzi and its mammalian replicative form.

Conclusions
The results retrieved in this study encourage further exploration of the chemical content of these extracts in search of new anti-T. cruzi drug development starting points.

Graphic abstract
Aedes species (Diptera: Culicidae) ecological and host feeding patterns in the north-eastern parts of South Africa, 2014–2018
Authors: Guarido M. M. , Riddin M. A. , Johnson T. , Braack L. E. O. , Schrama M. , Gorsich E. E. , Brooke B. D. , Almeida A. P. G. , Venter Marietjie 
Published: June 2021

Abstract
Background
There is a paucity of recent data and knowledge on mosquito diversity and potential vectors of arboviruses in South Africa, with most of the available data dating back to the 1950s–1970s. Aedes and Culex species are the major vectors of some of the principal arboviruses which have emerged and re-emerged in the past few decades.

Methods
In this study we used entomological surveillance in selected areas in the north-eastern parts of South Africa from 2014 to 2018 to assess mosquito diversity, with special emphasis on the Aedes species. The impact of trap types and environmental conditions was also investigated. Identification of the blood meal sources of engorged females collected during the study period was carried out, and DNA barcodes were generated for selected species.

Results
Overall, 18.5% of the total Culicidae mosquitoes collected belonged to the genus Aedes, with 14 species recognised or suspected vectors of arboviruses. Species belonging to the Neomelaniconion subgenus were commonly collected in the Bushveld savanna at conservation areas, especially Aedes mcintoshi and Aedes circumluteolus. Aedes aegypti was present in all sites, albeit in low numbers. Temperature was a limiting factor for the Aedes population, and they were almost exclusively collected at temperatures between 18 °C and 27 °C. The cytochrome oxidase subunit I (COI) barcode fragment was amplified for 21 Aedes species, and for nine of these species it was the first sequence information uploaded on GenBank.

Conclusion
This study provides a better understanding of the diversity and relative abundance of Aedes species in the north-east of South Africa. The information provided here will contribute to future arboviral research and implementation of efficient vector control and prevention strategies.

Graphical abstract
Serum fatty acid-binding protein 4 levels and responses of pancreatic islet β-cells and α-cells in patients with type 2 diabetes
Authors: Wang Hong , Cao Jie , Su Jian-bin , Wang Xue-qin , Wang Xing , Zhang Dong-mei , Wang Xiao-hua 
Published: June 2021

Abstract
Background
Serum fatty acid-binding protein 4 (FABP4), as an intracellular lipid chaperone and adipokine, was reported to be related to the incidence of type 2 diabetes (T2D) and diabetic complications, but its association with pancreatic islet β-cell and α-cell functions has not been fully elucidated. So the present study was to investigate the serum FABP4 levels and responses of islet β-cells and α-cells in patients with T2D.

Methods
115 patients with T2D and 89 healthy controls (HC), who received serum FABP4 levels test, were recruited to participate in this study. Moreover, 75-g oral glucose tolerance test (OGTT) was performed in T2D patients to evaluate islet β-cell and α-cell functions. Systemic insulin sensitivity and overall insulin secretion of islet β-cell function were assessed by Matsuda index using C peptide (ISIM-cp) and ratio of the area under the C peptide curve to the glucose curve (AUCcp/glu) during OGTT, respectively. Fasting glucagon (Gluca0min) and postchallenge glucagon assessed by the area under the glucagon curve (AUCgluca) were determined during OGTT to evaluate islet α-cell function. And other various clinical variables were also measured in all participants. Skewed variables were natural log-transformed (ln), such as lnFABP4.

Results
The serum FABP4 levels in T2D patients were significantly higher than those in HC (p < 0.05). And after partially adjusting for fasting plasma glucose, serum lnFABP4 levels were negatively correlated with lnISIM-cp (r =  − 0.332, p < 0.001) and positively correlated with lnAUCcp/glu (r = 0.324, p < 0.001), lnGluca0min (r = 0.200, p = 0.040) and lnAUCgluca (r = 0.311, p < 0.001), respectively, in patients with T2D. Furthermore, when multiple linear regression analyses were applied to adjust for other various clinical variables, serum lnFABP4 levels were found to remain associated with lnISIM-cp (β =  − 0.296, t =  − 2.900, p = 0.005), lnAUCcp/glu (β = 0.223, t = 2.038, p = 0.046), lnGluca0min (β = 0.272, t = 2.330, p = 0.024) and lnAUCgluca (β = 0.341, t = 3.065, p = 0.004), respectively.

Conclusion
Increased serum FABP4 levels were closely associated with blunted insulin sensitivity, increased insulin secretion, and elevated fasting and postchallenge glucagon levels in patients with T2D.
Arterial stiffness and progression of cerebral white matter hyperintensities in patients with type 2 diabetes and matched controls: a 5-year cohort study
Authors: Funck Kristian L. , Laugesen Esben , Høyem Pernille , Stausbøl-Grøn Brian , Kim Won Y. , Østergaard Leif , Grauballe Dora , Hansen Troels K. , Buhl Christian S. , Poulsen Per L. 
Published: June 2021

Abstract
Background
Stroke is a serious complication in patients with type 2 diabetes (T2DM). Arterial stiffness may improve stroke prediction. We investigated the association between carotid-femoral pulse wave velocity [PWV] and the progression of cerebral white matter hyperintensities (WMH), a marker of stroke risk, in patients with T2DM and controls.

Methods
In a 5-year cohort study, data from 45 patients and 59 non-diabetic controls were available for analysis. At baseline, participants had a mean (± SD) age of 59  ±  10 years and patients had a median (range) diabetes duration of 1.8 (0.8–3.2) years. PWV was obtained by tonometry and WMH volume by an automated segmentation algorithm based on cerebral T2-FLAIR and T1 MRI (corrected by intracranial volume, cWMH). High PWV was defined above 8.94 m/s (corresponding to the reference of high PWV above 10 m/s using the standardized path length method).

Results
Patients with T2DM had a higher PWV than controls (8.8  ±  2.2 vs. 7.9  ±  1.4 m/s, p  <  0.01). WMH progression were similar in the two groups (p  =  0.5). One m/s increase in baseline PWV was associated with a 16% [95% CI 1–32%], p  <  0.05) increase in cWMH volume at 5 years follow-up after adjustment for age, sex, diabetes, pulse pressure and smoking. High PWV was associated with cWMH progression in the combined cohort (p  <  0.05). We found no interaction between diabetes and PWV on cWMH progression.

Conclusions
PWV is associated with cWMH progression in patients with type 2 diabetes and non-diabetic controls. Our results indicate that arterial stiffness may be involved early in the pathophysiology leading to cerebrovascular diseases.
CRISPR/Cas9-based generation of a recombinant double-reporter pseudorabies virus and its characterization in vitro and in vivo
Authors: Fu Peng-Fei , Cheng Xuan , Su Bing-Qian , Duan Li-Fang , Wang Cong-Rong , Niu Xin-Rui , Wang Jiang , Yang Guo-Yu , Chu Bei-Bei 
Published: June 2021

AbstractPseudorabies, caused by pseudorabies virus (PRV) variants, has broken out among commercial PRV vaccine-immunized swine herds and resulted in major economic losses to the pig industry in China since late 2011. However, the mechanism of virulence enhancement of variant PRV is currently unclear. Here, a recombinant PRV (rPRV HN1201-EGFP-Luc) with stable expression of enhanced green fluorescent protein (EGFP) and firefly luciferase as a double reporter virus was constructed on the basis of the PRV variant HN1201 through CRISPR/Cas9 gene-editing technology coupled with two sgRNAs. The biological characteristics of the recombinant virus and its lethality to mice were similar to those of the parental strain and displayed a stable viral titre and luciferase activity through 20 passages. Moreover, bioluminescence signals were detected in mice at 12 h after rPRV HN1201-EGFP-Luc infection. Using the double reporter PRV, we also found that 25-hydroxycholesterol had a significant inhibitory effect on PRV both in vivo and in vitro. These results suggested that the double reporter PRV based on PRV variant HN1201 should be an excellent tool for basic virology studies and evaluating antiviral agents.
Proposing a reliable method of securing and verifying the credentials of graduates through blockchain
Authors: Rama Reddy T. , Prasad Reddy P. V. G. D. , Srinivas Rayudu , Raghavendran Ch. V. , Lalitha R. V. S. , Annapurna B. 
Published: June 2021

AbstractEducation acts as a soul in the overall societal development, in one way or the other. Aspirants, who gain their degrees genuinely, will help society with their knowledge and skills. But, on the other side of the coin, the problem of fake certificates is alarming and worrying. It has been prevalent in different forms from paper-based dummy certificates to replicas backed with database tampering and has increased to astronomic levels in this digital era. In this regard, an overlay mechanism using blockchain technology is proposed to store the genuine certificates in digital form and verify them firmly whenever needed without delay. The proposed system makes sure that the certificates, once verified, can be present online in an immutable form for further reference and provides a tamper-proof concealment to the existing certification system. To confirm the credibility of the proposed method, a prototype of blockchain-based credential securing and verification system is developed in ethereum test network. The implementation and test results show that it is a secure and feasible solution to online credential management system.