bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition
Authors: Breeur Marie , Ferrari Pietro , Dossus Laure , Jenab Mazda , Johansson Mattias , Rinaldi Sabina , Travis Ruth C. , His Mathilde , Key Tim J. , Schmidt Julie A. , Overvad Kim , Tjønneland Anne , Kyrø Cecilie , Rothwell Joseph A. , Laouali Nasser , Severi Gianluca , Kaaks Rudolf , Katzke Verena , Schulze Matthias B. , Eichelmann Fabian , Palli Domenico , Grioni Sara , Panico Salvatore , Tumino Rosario , Sacerdote Carlotta , Bueno-de-Mesquita Bas , Olsen Karina Standahl , Sandanger Torkjel Manning , Nøst Therese Haugdahl , Quirós J. Ramón , Bonet Catalina , Barranco Miguel Rodríguez , Chirlaque María-Dolores , Ardanaz Eva , Sandsveden Malte , Manjer Jonas , Vidman Linda , Rentoft Matilda , Muller David , Tsilidis Kostas , Heath Alicia K. , Keun Hector , Adamski Jerzy , Keski-Rahkonen Pekka , Scalbert Augustin , Gunter Marc J. , Viallon Vivian 
Published: October 2022

AbstractBackgroundEpidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations.MethodsWe analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty.ResultsOut of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk.ConclusionsThese results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.
Mitigation potential of individual and combined dietary supplementation of local Bentonite Clay and Distillery Sludge against Ochratoxin-A induced toxicity in broilers
Authors: Awais Mian Muhammad , Mehtab Ujala , Anwar Muhammad Irfan , Hameed Muhammad Raza , Akhtar Masood , Raza Ahmad , Aisha Riffat , Muhammad Faqir , Saleemi Muhammad Kashif , Fayyaz Ahad 
Published: October 2022

Abstract
Background
This study aimed to evaluate the ameliorative effects of dietary supplementation of local bentonite clay (BN) and distillery sludge (DS) alone and in combination on ochratoxin-A (OTA) induced toxicity in broilers. For this purpose, day-old-broiler chicks (n = 270) were procured from the local market and reared under standard management conditions. After 7 days of acclimatization, birds were divided into 2 main groups A and B with respect to OTA inclusion level in feed, each with four sub-groups viz. A1-A4, each challenged with OTA at a dietary inclusion level of 250 µg/kg feed and B1-B4, each challenged with OTA at the level of 500 µg/kg feed and a common control group that was fed with basal feed throughout the experiment. In groups A and B, BN and DS were administered with feed at the rate of 10 g/kg of feed and 5 g/kg of feed alone and in combination, respectively.

Results
Results showed that OTA administration alone resulted in poor feed conversion ratio (FCR) and immunological responses along with increased serum levels of alanine transaminase (ALT), Aspartate transaminase (AST), urea and creatinine (P < 0.05). A significant decrease (P < 0.05) in serum protein levels (albumin, globulin and total protein) was also observed in OTA-fed groups in a dose-dependent manner. The addition of BN at 10 g/kg of OTA-contaminated feed resulted in better FCR and immunological responses as compared to those fed OTA only. The BN supplementation also conferred protection against elevation of serum biochemical parameters when compared with OTA-fed groups. However, the addition of DS could not provide significant protection (P > 0.05) on alteration of serum biochemical parameters in response to the OTA induced toxicity. The combined supplementation of BN and DS resulted in amelioration of OTA-induced toxicity and showed improved FCR, immunological, hematological and serum biochemical parameters (P < 0.05) when compared with other groups. Similarly, BN and DS resulted in a significant decline (P < 0.05) in the OTA tissue residues compared with other groups and control.

Conclusion
In conclusion, combined dietary supplementation of BN (10 mg/kg) and DS (05 mg/kg) in feed reduced the toxic effects of OTA contamination at levels of 250 and 500 µg/kg of feed in broilers. So, the combination products of BN and DS may be successfully developed for use in poultry for protection against OTA-induced toxicity in broilers.
Tumor buster - where will the CAR-T cell therapy ‘missile’ go?
Authors: Qu Chunrun , Zhang Hao , Cao Hui , Tang Lanhua , Mo Haoyang , Liu Fangkun , Zhang Liyang , Yi Zhenjie , Long Lifu , Yan Luzhe , Wang Zeyu , Zhang Nan , Luo Peng , Zhang Jian , Liu Zaoqu , Ye Weijie , Liu Zhixiong , Cheng Quan 
Published: October 2022

AbstractChimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME) limit their use of it. Target selection is the most critical aspect in determining the prognosis of patients receiving this treatment. This review provides a comprehensive summary of all therapeutic targets used in the clinic or shown promising potential. We summarize CAR-T cell therapies’ clinical trials, applications, research frontiers, and limitations in treating different cancers. We also explore coping strategies when encountering sub-optimal tumor-associated antigens (TAA) or TAA loss. Moreover, the importance of CAR-T cell therapy in cancer immunotherapy is emphasized.
Prognostic significance of combined α-fetoprotein and CA19-9 for hepatocellular carcinoma after hepatectomy
Authors: Zhang Jie , Qin Shang Dong , Li Yan , Lu Fei , Gong Wen Feng , Zhong Jian Hong , Ma Liang , Zhao Jing Fei , Zhan Guo Hua , Li Peng Zhan , Song Bin , De Xiang Bang 
Published: October 2022

AbstractBackgroundThe prognosis of hepatocellular carcinoma (HCC) varies considerably among patients with the same disease stage and characteristics, and only about two thirds show high levels of α-fetoprotein (AFP), a common prognostic indicator for HCC. Here, we assessed whether the combination of presurgical serum levels of AFP and carbohydrate antigen 19-9 (CA19-9) can predict the prognosis of HCC patients after hepatectomy.MethodsThe clinicopathological characteristics and post-hepatectomy outcomes of 711 HCC patients were retrospectively reviewed. The patients were classified into three groups based on whether their preoperative serum levels of both AFP and CA19-9 were higher than the respective cut-offs of 400 ng/ml and 37 U/ml [double positive (DP)], the level of only one marker was higher than the cut-off [single positive (SP)], or neither level was higher than the cut-off [negative (N)]. The overall survival (OS) and recurrence-free survival (RFS) rates were estimated using Kaplan–Meier curves. Univariate and multivariate survival analyses were performed to identify the clinicopathological factors significantly associated with HCC prognosis.ResultsThe 1-year, 3-year, and 5-year RFS and OS rates in the N group were significantly higher than those in the SP group, while the DP group showed the lowest rates. Multivariate Cox regression analysis showed that large tumor size (> 5 cm), multiple tumors (≥ 2), incomplete tumor capsule, positive microvascular invasion, Barcelona Clinic Liver Cancer C stage, and CA19-9 level > 37 U/mL were independent risk factors for RFS and OS in HCC patients. Moreover, aspartate aminotransferase levels > 40 U/L proved to be an independent prognostic factor for OS.ConclusionThe combination of serum AFP and CA19-9 levels may be a useful prognostic marker for HCC patients after hepatectomy.
CapG promoted nasopharyngeal carcinoma cell motility involving Rho motility pathway independent of ROCK
Authors: Fu Ying , Zhang Xiuzhi , Liang Xujun , Chen Yongheng , Chen Zhuchu , Xiao Zhefeng 
Published: October 2022

Abstract
Background
Gelsolin-like capping actin protein (CapG) modulates actin dynamics and actin-based motility with a debatable role in tumorigenic progression. The motility-associated functions and potential molecular mechanisms of CapG in nasopharyngeal carcinoma (NPC) remain unclear.

Methods
CapG expression was detected by immunohistochemistry in a cohort of NPC tissue specimens and by Western blotting assay in a variety of NPC cell lines. Loss of function and gain of function of CapG in scratch wound-healing and transwell assays were performed. Inactivation of Rac1 and ROCK with the specific small molecular inhibitors was applied to evaluate CapG’s role in NPC cell motility. GTP-bound Rac1 and phosphorylated-myosin light chain 2 (p-MLC2) were measured in the ectopic CapG overexpressing cells. Finally, CapG-related gene set enrichment analysis was conducted to figure out the significant CapG-associated pathways in NPC.

Results
CapG disclosed increased level in the poorly differentiated NPC tissues and highly metastatic cells. Knockdown of CapG reduced NPC cell migration and invasion in vitro, while ectopic CapG overexpression showed the opposite effect. Ectopic overexpression of CapG compensated for the cell motility loss caused by simultaneous inactivation of ROCK and Rac1 or inactivation of ROCK alone. GTP-bound Rac1 weakened, and p-MLC2 increased in the CapG overexpressing cells. Bioinformatics analysis validated a positive correlation of CapG with Rho motility signaling, while Rac1 motility pathway showed no significant relationship.

Conclusions
The present findings highlight the contribution of CapG to NPC cell motility independent of ROCK and Rac1. CapG promotes NPC cell motility at least partly through MLC2 phosphorylation and contradicts with Rac1 activation.
Lrpap1 deficiency leads to myopia through TGF-β-induced apoptosis in zebrafish
Authors: Liu Shanshan , Chen Ting , Chen Binghao , Liu Yijun , Lu Xiaohe , Li Jiali 
Published: October 2022

Abstract
Background
Frameshift mutations in LRPAP1 are responsible for autosomal recessive high myopia in human beings but its underlying mechanism remains elusive. This study aims to investigate the effect of LRPAP1 defect on ocular refractive development and its involved mechanism.

Methods
A lrpap1 mutant zebrafish line with homozygous frameshift mutation was generated by CRISPR/Cas9 technology and confirmed by Sanger sequencing. The ocular refractive phenotype was analyzed by calculating the relative refractive error (RRE) with vivo photography and histological analysis at different development stages, together with examining ocular structure change via transmission electron microscopy. Further, RNA sequencing and bioinformatics analysis were performed. The potentially involved signaling pathway as well as the interacted protein were investigated in vivo.

Results
The lrpap1 homozygous mutant zebrafish line showed myopic phenotype. Specifically, the mutant lines showed larger eye axial length-to-body length in one-month old individuals and a myopic shift with an RRE that changed after two months. Collagen fibers became thinning and disordered in the sclera. Further, RNA sequencing and bioinformatics analysis indicated that apoptosis signaling was activated in mutant line; this was further confirmed by acridine orange and TUNEL staining. Moreover, the expression of TGF-β protein was elevated in the mutant lines. Finally, the treatment of wild-type embryos with a TGF-β agonist aggravated the degree of eyeball apoptosis; conversely, the use of a TGF-β inhibitor mitigated apoptosis in mutant embryos.

Conclusion
The study provides functional evidence of a link between lrpap1 and myopia, suggesting that lrpap1 deficiency could lead to myopia through TGF-β-induced apoptosis signaling.
LotuS2: an ultrafast and highly accurate tool for amplicon sequencing analysis
Authors: Özkurt Ezgi , Fritscher Joachim , Soranzo Nicola , Ng Duncan Y. K. , Davey Robert P. , Bahram Mohammad , Hildebrand Falk 
Published: October 2022

Abstract
Background
Amplicon sequencing is an established and cost-efficient method for profiling microbiomes. However, many available tools to process this data require both bioinformatics skills and high computational power to process big datasets. Furthermore, there are only few tools that allow for long read amplicon data analysis. To bridge this gap, we developed the LotuS2 (less OTU scripts 2) pipeline, enabling user-friendly, resource friendly, and versatile analysis of raw amplicon sequences.

Results
In LotuS2, six different sequence clustering algorithms as well as extensive pre- and post-processing options allow for flexible data analysis by both experts, where parameters can be fully adjusted, and novices, where defaults are provided for different scenarios.
We benchmarked three independent gut and soil datasets, where LotuS2 was on average 29 times faster compared to other pipelines, yet could better reproduce the alpha- and beta-diversity of technical replicate samples. Further benchmarking a mock community with known taxon composition showed that, compared to the other pipelines, LotuS2 recovered a higher fraction of correctly identified taxa and a higher fraction of reads assigned to true taxa (48% and 57% at species; 83% and 98% at genus level, respectively). At ASV/OTU level, precision and F-score were highest for LotuS2, as was the fraction of correctly reported 16S sequences.

Conclusion
LotuS2 is a lightweight and user-friendly pipeline that is fast, precise, and streamlined, using extensive pre- and post-ASV/OTU clustering steps to further increase data quality. High data usage rates and reliability enable high-throughput microbiome analysis in minutes.

Availability
LotuS2 is available from GitHub, conda, or via a Galaxy web interface, documented at http://lotus2.earlham.ac.uk/.
Study on the efficacy of amorphous calcium carbonate as a consolidant for calcareous matrix
Authors: Wang Wenwen , Wang Shuzhe , Liu Qiang , Wang Xiaofei , Zhu Jianfeng , Luo Hongjie , Ji Shidong 
Published: October 2022

Abstract
The popular involvement of amorphous calcium carbonate (ACC) in organisms, usually via a complicated non-classical crystallization pathway, has aroused interest in the scientific community. In recent years, a lot of work has been carried out for the preparation and application of ACC. In this paper, the effectiveness of ACC for the consolidation of calcareous matrix was evaluated. ACC was synthesized through direct carbonation of calcium oxide in ethanol and was introduced into simulated samples as consolidant. A comprehensive study for the assessment of protective effect was carried out by testing surface strength, chromaticity, compressive strength, water vapor permeability, water absorption and freezing–thawing resistance. The results showed that the addition of ACC could significantly improve the surface strength, compressive strength and weatherability of treated samples, while it had only a slight influence on color difference and water vapor permeability. It was confirmed that ACC could connect the loose calcite particles by ‘spot welding’ through heterogeneous nucleation and growth processes. As a consolidant, it demonstrated its merits in this study and could be proposed as an alternative for the protection of weathered calcareous stones.
Electric field responsive nanotransducers for glioblastoma
Authors: Jain Akhil , Jobson Isobel , Griffin Michaela , Rahman Ruman , Smith Stuart , Rawson Frankie J. 
Published: October 2022

Abstract
Background
Electric field therapies such as Tumor Treating Fields (TTFields) have emerged as a bioelectronic treatment for isocitrate dehydrogenase wild-type and IDH mutant grade 4 astrocytoma Glioblastoma (GBM). TTFields rely on alternating current (AC) electric fields (EF) leading to the disruption of dipole alignment and induced dielectrophoresis (DEP) during cytokinesis. Although TTFields have a favourable side effect profile, particularly compared to cytotoxic chemotherapy, survival benefits remain limited (~ 4.9 months) after an extensive treatment regime (20 hours/day for 18 months). The cost of the technology also limits its clinical adoption worldwide. Therefore, the discovery of new technology that can enhance both the therapeutic efficiency and efficacy of these TTFields will be of great benefit to cancer treatment and decrease healthcare costs worldwide.

Methods
In this work, we report the role of electrically conductive gold (GNPs), dielectric silica oxide (SiO2), and semiconductor zinc oxide (ZnO) nanoparticles (NPs) as transducers for enhancing EF mediated anticancer effects on patient derived GBM cells. Physicochemical properties of these NPs were analyzed using spectroscopic, electron microscopy, and light-scattering techniques.

Results
In vitro TTFields studies indicated an enhanced reduction in the metabolic activity of patient-derived Glioma INvasive marginal (GIN 28) and Glioma contrast enhanced core (GCE 28) GBM cells in groups treated with NPs vs. control groups, irrespective of NPs dielectric properties. Our results indicate the inorganic NPs used in this work enhance the intracellular EF effects that could be due to the virtue of bipolar dielectrophoretic and electrophoretic effects.

Conclusions
This work presents preliminary evidence which could help to improve future EF applications for bioelectronic medicine. Furthermore, the merits of spherical morphology, excellent colloidal stability, and low toxicity, make these NPs ideal for future studies for elucidating the detailed mechanism and efficacy upon their delivery in GBM preclinical models.
NRG Oncology/RTOG1205: A Randomized Phase II Trial of Concurrent Bevacizumab and Reirradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma
Authors: Tsien Christina I. , Pugh Stephanie L. , Dicker Adam P. , Raizer Jeffrey J. , Matuszak Martha M. , Lallana Enrico C. , Huang Jiayi , Algan Ozer , Deb Nimisha , Portelance Lorraine , Villano John L. , Hamm John T. , Oh Kevin S. , Ali Arif N. , Kim Michelle M. , Lindhorst Scott M. , Mehta Minesh P. 
Published: October 2022

PURPOSETo assess whether reirradiation (re-RT) and concurrent bevacizumab (BEV) improve overall survival (OS) and/or progression-free survival (PFS), compared with BEV alone in recurrent glioblastoma (GBM). The primary objective was OS, and secondary objectives included PFS, response rate, and treatment adverse events (AEs) including delayed CNS toxicities.METHODSNRG Oncology/RTOG1205 is a prospective, phase II, randomized trial of re-RT and BEV versus BEV alone. Stratification factors included age, resection, and Karnofsky performance status (KPS). Patients with recurrent GBM with imaging evidence of tumor progression ≥ 6 months from completion of prior chemo-RT were eligible. Patients were randomly assigned 1:1 to re-RT, 35 Gy in 10 fractions, with concurrent BEV IV 10 mg/kg once in every 2 weeks or BEV alone until progression.RESULTSFrom December 2012 to April 2016, 182 patients were randomly assigned, of whom 170 were eligible. Patient characteristics were well balanced between arms. The median follow-up for censored patients was 12.8 months. There was no improvement in OS for BEV + RT, hazard ratio, 0.98; 80% CI, 0.79 to 1.23; P = .46; the median survival time was 10.1 versus 9.7 months for BEV + RT versus BEV alone. The median PFS for BEV + RT was 7.1 versus 3.8 months for BEV, hazard ratio, 0.73; 95% CI, 0.53 to 1.0; P = .05. The 6-month PFS rate improved from 29.1% (95% CI, 19.1 to 39.1) for BEV to 54.3% (95% CI, 43.5 to 65.1) for BEV + RT, P = .001. Treatment was well tolerated. There were a 5% rate of acute grade 3+ treatment-related AEs and no delayed high-grade AEs. Most patients died of recurrent GBM.CONCLUSIONTo our knowledge, NRG Oncology/RTOG1205 is the first prospective, randomized multi-institutional study to evaluate the safety and efficacy of re-RT in recurrent GBM using modern RT techniques. Overall, re-RT was shown to be safe and well tolerated. BEV + RT demonstrated a clinically meaningful improvement in PFS, specifically the 6-month PFS rate but no difference in OS.
Autopsy Study of Testicles in COVID-19: Upregulation of Immune-Related Genes and Downregulation of Testis-Specific Genes
Authors: Basolo Alessio , Poma Anello Marcello , Macerola Elisabetta , Bonuccelli Diana , Proietti Agnese , Salvetti Alessandra , Vignali Paola , Torregrossa Liborio , Evangelisti Laura , Sparavelli Rebecca , Giannini Riccardo , Ugolini Clara , Basolo Fulvio , Santini Ferruccio , Toniolo Antonio 
Published: October 2022

AbstractContextInfection by SARS-CoV-2 may be associated with testicular dysfunction that could affect male fertility.ObjectiveTesticles of fatal COVID-19 cases were investigated to detect virus in tissue and to evaluate histopathological and transcriptomic changes.MethodsThree groups were compared: (a) uninfected controls (subjects dying of trauma or sudden cardiac death; n = 10); (b) subjects dying of COVID-19 (virus-negative in testes; n = 15); (c) subjects dying of COVID-19 (virus-positive in testes; n = 9). SARS-CoV-2 genome and nucleocapsid antigen were probed using RT-PCR, in situ hybridization, and immunohistochemistry (IHC). Infiltrating leukocytes were typed by IHC. mRNA transcripts of immune-related and testis-specific genes were quantified using the nCounter method.ResultsSARS-CoV-2 was detected in testis tissue of 9/24 (37%) COVID-19 cases accompanied by scattered T-cell and macrophage infiltrates. Size of testicles and counts of spermatogenic cells were not significantly different among groups. Analysis of mRNA transcripts showed that in virus-positive testes immune processes were activated (interferon-alpha and -gamma pathways). By contrast, transcription of 12 testis-specific genes was downregulated, independently of virus positivity in tissue. By IHC, expression of the luteinizing hormone/choriogonadotropin receptor was enhanced in virus-positive compared to virus-negative testicles, while expression of receptors for androgens and the follicle-stimulating hormone were not significantly different among groups.ConclusionIn lethal COVID-19 cases, infection of testicular cells is not uncommon. Viral infection associates with activation of interferon pathways and downregulation of testis-specific genes involved in spermatogenesis. Due to the exceedingly high numbers of infected people in the pandemic, the impact of virus on fertility should be further investigated.