bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adding rituximab to chemotherapy for diffuse large B-cell lymphoma patients in Indonesia: a cost utility and budget impact analysis
Authors: Putri Septiara , Setiawan Ery , Saldi Siti Rizny F. , Khoe Levina Chandra , Sari Euis Ratna , Megraini Amila , Nadjib Mardiati , Sastroasmoro Sudigdo , Armansyah Armansyah 
Published: April 2022

Abstract
Background
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been used to treat patients with diffuse large B-cell lymphoma (DLBCL) under National Health Insurance (NHI) scheme in Indonesia. This study aims to estimate its cost-effectiveness and budget impact.

Methods
We conducted a cost utility analysis using Markov model over a lifetime horizon, from a societal perspective. Clinical evidence was derived from published clinical trials. Direct medical costs were gathered from hospital data. Direct non-medical costs, indirect costs, and utility data were primarily gathered by interviewing the patients. We applied 3% discount rate for both costs and effect. All monetary data are converted into USD (1 USD = IDR 14,000, 2019). Probabilistic sensitivity analysis was performed. In addition, from a payer perspective, budget impact analysis was estimated using price reduction scenarios.

Results
The incremental cost-effectiveness ratio (ICER) of R-CHOP was USD 4674/LYG and 9280/QALY. If we refer to the threshold three times the GDP per capita (USD 11,538), R-CHOP could thus be determined as a cost-effective therapy. Its significant health benefit has contributed to the considerable ICER result. Although the R-CHOP has been considered a cost-effective intervention, the financial consequence of R-CHOP if remain in benefit package under National Health Insurance (NHI) system in Indonesia is considerably substantial, approximately USD 35.00 million with 75% price reduction scenario.

Conclusions
As a favorable treatment for DLBCL, R-CHOP ensures value for money in Indonesia. Budget impact analysis provides results which can be used as further consideration for decision-makers in matters related to benefit packages.
Phylogenomic approaches untangle early divergences and complex diversifications of the olive plant family
Authors: Dong Wenpan , Li Enze , Liu Yanlei , Xu Chao , Wang Yushuang , Liu Kangjia , Cui Xingyong , Sun Jiahui , Suo Zhili , Zhang Zhixiang , Wen Jun , Zhou Shiliang 
Published: April 2022

AbstractBackgroundDeep-branching phylogenetic relationships are often difficult to resolve because phylogenetic signals are obscured by the long history and complexity of evolutionary processes, such as ancient introgression/hybridization, polyploidization, and incomplete lineage sorting (ILS). Phylogenomics has been effective in providing information for resolving both deep- and shallow-scale relationships across all branches of the tree of life. The olive family (Oleaceae) is composed of 25 genera classified into five tribes with tribe Oleeae consisting of four subtribes. Previous phylogenetic analyses showed that ILS and/or hybridization led to phylogenetic incongruence in the family. It was essential to distinguish phylogenetic signal conflicts, and explore mechanisms for the uncertainties concerning relationships of the olive family, especially at the deep-branching nodes.ResultsWe used the whole plastid genome and nuclear single nucleotide polymorphism (SNP) data to infer the phylogenetic relationships and to assess the variation and rates among the main clades of the olive family. We also used 2608 and 1865 orthologous nuclear genes to infer the deep-branching relationships among tribes of Oleaceae and subtribes of tribe Oleeae, respectively. Concatenated and coalescence trees based on the plastid genome, nuclear SNPs and multiple nuclear genes suggest events of ILS and/or ancient introgression during the diversification of Oleaceae. Additionally, there was extreme heterogeneity in the substitution rates across the tribes. Furthermore, our results supported that introgression/hybridization, rather than ILS, is the main factor for phylogenetic discordance among the five tribes of Oleaceae. The tribe Oleeae is supported to have originated via ancient hybridization and polyploidy, and its most likely parentages are the ancestral lineage of Jasmineae or its sister group, which is a “ghost lineage,” and Forsythieae. However, ILS and ancient introgression are mainly responsible for the phylogenetic discordance among the four subtribes of tribe Oleeae.ConclusionsThis study showcases that using multiple sequence datasets (plastid genomes, nuclear SNPs and thousands of nuclear genes) and diverse phylogenomic methods such as data partition, heterogeneous models, quantifying introgression via branch lengths (QuIBL) analysis, and species network analysis can facilitate untangling long and complex evolutionary processes of ancient introgression, paleopolyploidization, and ILS.
Comprehensive analysis of prognostic value and immune infiltration of CXC chemokines in pancreatic cancer
Authors: Jing Yanhua , Wang Fengjiao , Zhang Ke , Chen Zhen 
Published: April 2022

Abstract
Background
The prognosis of pancreatic cancer is poor, with a 5-year survival rate of less than 10%. Studies have shown that chemokines in the tumour microenvironment are often altered, which is associated with immune infiltration and the prognosis and survival of pancreatic cancer patients.

Methods
Multiomics and bioinformatics tools were used to clarify CXC chemokine expression and its role in the pancreatic ductal adenocarcinoma (PDAC) immune microenvironment.

Results
Most CXC chemokines were upregulated in pancreatic cancer and correlated with patient prognosis. CXC chemokines can activate cancer-related signalling pathways and affect immune infiltration. Furthermore, most CXC chemokines were significantly correlated with the abundance of macrophages, neutrophils and dendritic cells. CXCL5 was selected as a hub gene, and a variety of immune checkpoints, including PD-1/PD-L1 and CTLA-4, were identified.

Conclusion
Our study provides novel insights into CXC chemokine expression and its role in the PDAC immune microenvironment. These results can provide more data about prognostic biomarkers and therapeutic targets of PDAC.
Genotypic and phenotypic diversity among Komagataella species reveals a hidden pathway for xylose utilization
Authors: Heistinger Lina , Dohm Juliane C. , Paes Barbara G. , Koizar Daniel , Troyer Christina , Ata Özge , Steininger-Mairinger Teresa , Mattanovich Diethard 
Published: April 2022

AbstractBackgroundThe yeast genusKomagataellacurrently consists of seven methylotrophic species isolated from tree environments. Well-characterized strains ofK. phaffiiandK. pastorisare important hosts for biotechnological applications, but the potential of other species from the genus remains largely unexplored. In this study, we characterized 25 natural isolates from all seven describedKomagataellaspecies to identify interesting traits and provide a comprehensive overview of the genotypic and phenotypic diversity available within this genus.ResultsGrowth tests on different carbon sources and in the presence of stressors at two different temperatures allowed us to identify strains with differences in tolerance to high pH, high temperature, and growth on xylose. AsKomagataellaspecies are generally not considered xylose-utilizing yeasts, xylose assimilation was characterized in detail. Growth assays, enzyme activity measurements and13C labeling confirmed the ability ofK. phaffiito utilize D-xylose via the oxidoreductase pathway. In addition, we performed long-read whole-genome sequencing to generate genome assemblies of allKomagataellaspecies type strains and additionalK. phaffiiandK. pastorisisolates for comparative analysis. All sequenced genomes have a similar size and share 83–99% average sequence identity. Genome structure analysis showed thatK. pastorisandK. ulmishare the same rearrangements in difference toK. phaffii, while the genome structure ofK. kurtzmaniiis similar toK. phaffii. The genomes of the other, more distant species showed a larger number of structural differences. Moreover, we used the newly assembled genomes to identify putative orthologs of important xylose-related genes in the differentKomagataellaspecies.ConclusionsBy characterizing the phenotypes of 25 naturalKomagataellaisolates, we could identify strains with improved growth on different relevant carbon sources and stress conditions. Our data on the phenotypic and genotypic diversity will provide the basis for the use of so-far neglectedKomagataellastrains with interesting characteristics and the elucidation of the genetic determinants of improved growth and stress tolerance for targeted strain improvement.
Human neural stem cell-derived extracellular vesicles protect against Parkinson’s disease pathologies
Authors: Lee Eun Ji , Choi Yoori , Lee Hong J. , Hwang Do Won , Lee Dong Soo 
Published: April 2022

Abstract
Background
Neural stem cells (NSCs) have the ability to generate a variety of functional neural cell types and have a high potential for neuronal cell regeneration and recovery. Thus, they been recognized as the best source of cell therapy for neurodegenerative diseases, such as Parkinson’s disease (PD). Owing to the possibility of paracrine effect-based therapeutic mechanisms and easier clinical accessibility, extracellular vesicles (EVs), which possess very similar bio-functional components from their cellular origin, have emerged as potential alternatives in regenerative medicine.

Material and methods
EVs were isolated from human fibroblast (HFF) and human NSC (F3 cells). The supernatant of the cells was concentrated by a tangential flow filtration (TFF) system. Then, the final EVs were isolated using a total EV isolation kit.

Results
In this study, we demonstrate the potential protective effect of human NSC-derived EVs, showing the prevention of PD pathologies in 6-hydroxydopamine (6-OHDA)-induced in vitro and in vivo mouse models. Human NSC and F3 cell (F3)-derived EVs reduced the intracellular reactive oxygen species (ROS) and associated apoptotic pathways. In addition, F3-derived EVs induced downregulation of pro-inflammatory factors and significantly decreased 6-OHDA-induced dopaminergic neuronal loss in vivo. F3 specific microRNAs (miRNAs) such as hsa-mir-182-5p, hsa-mir-183-5p, hsa-mir-9, and hsa-let-7, which are involved in cell differentiation, neurotrophic function, and immune modulation, were found in F3-derived EVs.

Conclusions
We report that human NSC-derived EVs show an effective neuroprotective property in an in vitro transwell system and in a PD model. The EVs clearly decreased ROS and pro-inflammatory cytokines. Taken together, these results indicate that NSC-derived EVs could potentially help prevent the neuropathology and progression of PD.

Graphical Abstract
TMT-based proteomics analysis of the cerebral cortex of TauT knockout rats
Authors: Xia Yiming , Huang Xiaoling , Mo Lidong , Wang Chen , Fan Weijia , Huang Huiling 
Published: April 2022

Abstract
Background
Taurine serves a variety of nutritional and physiological roles, and it is mostly transported in cells via taurine transporter (TauT). The effect of taurine transporter in cerebral cortex is still unknown. We employed TMT label-based proteomics to find differences in proteins in the cerebral cortex of TauT knockout rats in this investigation. The goal of this research was to see how TauT deletion affected protein alterations in brain tissue and to see if there was a new research area for TauT.

Methods
The cerebral cortex of TauT knockout rats and wild-type control rats were analyzed using TMT-based proteomics, and differentially expressed proteins were analyzed by bioinformatics analysis means such as GO and KEGG, the association between the proteins was found by PPI, and biologically significant and interesting proteins were selected for verification by WB and immunohistochemistry.

Results
There were total of 8275 proteins found, but only 35 differentially expressed proteins were identified (27 up-regulated and 8 down-regulated), and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the biological pathways and functional classification of the proteins. The results show that these differentially expressed proteins are mainly enriched in lysine degradation, cell cycle, chronic myeloid leukemia, and longevity regulating pathways-multiple species, renal cell carcinoma, pathways in cancer, etc. To verify the proteomic data, we analyzed the expression of Annexin6 and Pik3r2 by western blotting and immunofluorescence. The results are consistent with proteomics, which proves the reliability of our proteomics data.

Conclusion
Through TMT-based proteomics, we have a comprehensive understanding of the effect of TauT knockout on the changes of other proteins in the cerebral cortex, providing new evidence for further understanding the function of TauT.
The need for uniform and coordinated practices involving centrally manufactured cell therapies
Authors: Stroncek David , Dinh Anh , Rai Herleen , Zhang Nan , Somerville Rob , Panch Sandhya 
Published: April 2022

AbstractCellular therapies have become an important part of clinical care. The treatment of patients with cell therapies often involves the collection of autologous cells at the medical center treating the patient, the shipment of these cells to a centralized manufacturing site, and the return of the cryopreserved clinical cell therapy to the medical center treating the patient for storage until infusion. As this activity grows, cell processing laboratories at many academic medical centers are involved with many different autologous products manufactured by several different centralized laboratories. The handling of these products by medical center-based cell therapy laboratories is complicated and resource-intensive since each centralized manufacturing laboratory has unique methods for labeling, storing, shipping, receiving, thawing, and infusing the cells. The field would benefit from the development of more uniform practices. The development of a coordinating center similar to those established to facilitate the collection, shipping, and transplantation of hematopoietic stem cells from unrelated donors would also be beneficial. In summary, the wide range of practices involved with labeling, shipping, freezing, thawing, and infusing centrally manufactured autologous cellular therapies lack efficiency and consistency and puts patients at risk. More uniform practices are needed.
Identification of molecular subtypes and a novel prognostic model of diffuse large B-cell lymphoma based on a metabolism-associated gene signature
Authors: He Jing , Chen Ziwei , Xue Qingfeng , Sun Pingping , Wang Yuan , Zhu Cindy , Shi Wenyu 
Published: April 2022

Abstract
Background
Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma in adults. Metabolic reprogramming in tumors is closely related to the immune microenvironment. This study aimed to explore the interactions between metabolism-associated genes (MAGs) and DLBCL prognosis and their potential associations with the immune microenvironment.

Methods
Gene expression and clinical data on DLBCL patients were obtained from the GEO database. Metabolism-associated molecular subtypes were identified by consensus clustering. A prognostic risk model containing 14 MAGs was established using Lasso-Cox regression in the GEO training cohort. It was then validated in the GEO internal testing cohort and TCGA external validation cohort. GO, KEGG and GSVA were used to explore the differences in enriched pathways between high- and low-risk groups. ESTIMATE, CIBERSORT, and ssGSEA analyses were used to assess the immune microenvironment. Finally, WGCNA analysis was used to identify two hub genes among the 14 model MAGs, and they were preliminarily verified in our tissue microarray (TMA) using multiple fluorescence immunohistochemistry (mIHC).

Results
Consensus clustering divided DLBCL patients into two metabolic subtypes with significant differences in prognosis and the immune microenvironment. Poor prognosis was associated with an immunosuppressive microenvironment. A prognostic risk model was constructed based on 14 MAGs and it was used to classify the patients into two risk groups; the high-risk group had poorer prognosis and an immunosuppressive microenvironment characterized by low immune score, low immune status, high abundance of immunosuppressive cells, and high expression of immune checkpoints. Cox regression, ROC curve analysis, and a nomogram indicated that the risk model was an independent prognostic factor and had a better prognostic value than the International Prognostic Index (IPI) score. The risk model underwent multiple validations and the verification of the two hub genes in TMA indicated consistent results with the bioinformatics analyses.

Conclusions
The molecular subtypes and a risk model based on MAGs proposed in our study are both promising prognostic classifications in DLBCL, which may provide novel insights for developing accurate targeted cancer therapies.
Effect of GOAL-Directed ANalgesia using ANI (Analgesia/Nociception Index) during general anesthesia on immediate postoperative pain and intraoperative hemodynamics in adult patients (GOALDAN study): a study protocol for randomized, controlled, multicenter trial
Authors: Michalot Adrien , Bazin Jean-Étienne , Richebé Philippe , Allaouchiche Bernard , Boselli Emmanuel 
Published: April 2022

AbstractBackgroundSevere postoperative pain remains a major problem that is seen in 20 to 40% of patients. The Analgesia/Nociception Index (ANI) is a 0–100 index reflecting the relative parasympathetic activity allowing for intraoperative analgesia monitoring. We have previously shown that an ANI value < 50 immediately before extubation may predict the occurrence of immediate postoperative pain with good performance. We hypothesized that GOAL-Directed ANalgesia may provide reduced immediate postoperative pain and optimized intraoperative remifentanil administration (GOLDAN study).MethodsThe GOALDAN study is an international, multicenter, simple-blind, parallel, prospective, randomized, controlled, two-armed trial. Patients are randomly assigned in a 1:1 ratio in the control group or in the experimental group. Patients will be randomly allocated to either the intervention group (ANI) or the control group (standard care only). In the ANI group, the administration of remifentanil will be goal-directed targeting a 50–80 ANI range, with a prophylactic injection of morphine immediately after extubation if the case of ANI < 50. Our primary objective was to determine whether the prophylactic administration of morphine at the end of the procedure in patients at risk of immediate postoperative pain (ANI < 50 immediately before extubation) could reduce the incidence of the latter by 50% in the post-anesthetic care unit. Our secondary objective was to determine whether the intraoperative use of goal-directed analgesia with an ANI target of 50 to 80 could improve intraoperative hemodynamics and postoperative outcome.DiscussionBecause of the paucity of well-conducted trials, the authors believe that a randomized-controlled trial will improve the evidence for using analgesia monitoring during general anesthesia and strengthen current recommendations for intraoperative analgesia management.Trial registrationClinicalTrials.govNCT03618082. Registered on 7 August 2018
Highly efficient biosynthesis of β-caryophyllene with a new sesquiterpene synthase from tobacco
Authors: Cheng Tao , Zhang Kai , Guo Jing , Yang Qing , Li Yiting , Xian Mo , Zhang Rubing 
Published: April 2022

Abstract
Background
β-Caryophyllene, a kind of bicyclic sesquiterpene, is mainly used as a spice in the food and cosmetic industries. Furthermore, it also has significant value in the pharmaceutical industry and is now considered to be used as a new fuel. As a chemical energy heterotrophic microorganism, Escherichia coli can produce a large amount of acetyl-CoA through aerobic respiration, and acetyl-CoA is the common precursor substance in the biosynthesis of all terpenoids. Therefore, E. coli has the potential to be a cell factory to produce terpenoids.

Results
A new gene of β-caryophyllene synthase (TPS7) was found by analyzing the genome of Nicotiana tabacum L. using bioinformatics methods. The gene was overexpressed in engineered E. coli with a heterogeneous mevalonate (MVA) pathway to build a recombinant strain CAR1. Subsequent cultivation experiments in shake flask of engineered strain CAR1 verified that 16.1 mg/L β-caryophyllene was detected from the fermentation broth in the shake flask after induction for 24 h with IPTG. The toxic by-product of farnesyl acetate was detected during the process, and CAR1 showed a heavily cellular accumulation of product. We constructed an engineered strain CAR2, in which the downstream genes of the MVA pathway were integrated into the E. coli chromosome, successfully increasing β-caryophyllene production to 100.3 mg/L. The highest production of β-caryophyllene during the fed-batch fermentation was 4319 mg/L. Then we employed in situ extraction fermentation to successfully increase the production of β-caryophyllene by 20% to 5142 mg/L.

Conclusion
A new sesquiterpene synthase, TPS7, from tobacco was found to be able to produce β-caryophyllene with high efficiency. Based on this, an engineered E. coli was constructed to produce a much higher concentration of β-caryophyllene than the previous studies. During the fermentation process, we observed that β-caryophyllene tends to accumulate in intracellular space, which will eventually influence the activity of engineered E. coli. As a result, we solved this by metabolism regulation and in situ extractive fermentation.
Improving the reproducibility and integrity of research: what can different stakeholders contribute?
Authors: Macleod Malcolm ,   the University of Edinburgh Research Strategy Group
Published: April 2022

AbstractIncreasing awareness of problems with the reproducibility and integrity of research led the UK Parliament Science and Technology Committee to launch, in July 2021, an inquiry into reproducibility and research integrity. We recognise at least four potential reasons why attempts to replicate a research finding may be unsuccessful: false positive statistical analyses, low generalisability of findings, suboptimal study designs (research integrity), and deliberate malfeasance (researcher integrity). It is important to make a distinction between the contributions of research integrity and of researcher integrity to the reproducibility crisis. While the impact of an individual instance of compromised researcher integrity is substantial, the aggregate impact of more prevalent problems with research integrity is likely much greater. The research community will be most efficient when failed replication efforts are never due to issues of research integrity or of researcher integrity, as this would allow focus on the scientific reasons for why two apparently similar experiments should reach different conclusions. We discuss the role of funders, institutions and government in addressing the “reproducibility crisis” before considering which interventions might have a positive impact on academia’s approach to reproducible research, and a possible role for a committee on research integrity.
Multilinear strongly singular integral operators on non-homogeneous metric measure spaces
Authors: Wang Hailian , Xie Rulong 
Published: April 2022

AbstractLet $(X,d,\mu )$
(
X
,
d
,
μ
)
be a non-homogeneous metric measure space satisfying the geometrically and upper doubling measure conditions. In this paper, the boundedness in Lebesgue spaces for multilinear strongly singular integral operators on non-homogeneous metric measure spaces is proved. As an application, the boundedness in Morrey spaces for multilinear strongly singular integral operators is also obtained.