bluuebunny/crossref_metadata_2025 huggingface dataset:
A Benchmark Side-by-Side Comparison of Two Well-Established Protocols for in vitro Hematopoietic Differentiation From Human Pluripotent Stem Cells
Authors: Gutierrez-Agüera Francisco , Rodriguez-Cortez Virginia , Petazzi Paolo , Bueno Clara , Menendez Pablo
Published: May 2021

The generation of transplantable hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) remains challenging. Current differentiation protocols from hPSCs generate mostly hematopoietic progenitors of the primitive HSC-independent program, and it remains unclear what is the best combination of cytokines and hematopoietic growth factors (HGFs) for obtaining functional hematopoietic cells in vitro. Here, we have used the AND1 and H9 hESC lines and the H9:dual-reporter RUNX1C-GFP-SOX17-Cherry to compare the hematopoietic differentiation in vitro based on the treatment of embryoid bodies (EBs) with the ventral mesoderm inducer BMP4 plus HGFs in the absence (protocol 1) or presence (protocol 2) of stage-specific activation of Wnt/β-catenin and inhibition of Activin/Nodal. Despite a slight trend in favor of protocol 1, no statistically significant differences were observed between protocols at any time point analyzed throughout EB development regarding the frequency of hemogenic endothelial (HE) precursors; CD43+ CD45−, CD45+, and CD45 + CD34 + hematopoietic derivatives; or the output of clonogenic progenitors. Similarly, the kinetics of emergence throughout EB development of both SOX17 + HE and RUNX1C + definitive hematopoiesis was very similar for both protocols. The expression of the early master mesendodermal transcription factors Brachyury, MIXL1, and KDR revealed similar gene expression kinetics prior to the emergence of RUNX1C + definitive hematopoiesis for both protocols. Collectively, the simpler protocol 1 is, at least, as efficient as protocol 2, suggesting that supplementation with additional morphogens/HGFs and modulation of Activin/Nodal and Wnt/β-catenin pathways seem dispensable for in vitro hematopoietic differentiation of hPSCs.
Activin A as a Novel Chemokine Induces Migration of L929 Fibroblasts by ERK Signaling in Microfluidic Devices
Authors: Jiang Lingling , Qi Yan , Kong Xianghan , Wang Runnan , Qi Jianfei , Lin Francis , Cui Xueling , Liu Zhonghui
Published: May 2021

Activin A, a member of the transforming growth factor-beta (TGF-β) superfamily, contributes to tissue healing and fibrosis. As the innate tissue cells, fibroblasts also play an important role in wound healing and fibrosis. Herein, this study was aimed to investigate how activin A exhibited regulatory effects on adhesion and migration of fibroblasts. We found that activin A induced the migration of fibroblast cell line L929 cells in transwell chamber and microfluidic device. Activin A also promoted L929 cells adhesion, but did not affect L929 cells viability or proliferation. In addition, activin A induced α-SMA expression and TGF-β1 release, which were factors closely related to tissue fibrosis, but had no effect on IL-6 production, a pro-inflammatory cytokine. Furthermore, activin A elevated calcium levels in L929 cells and increased p-ERK protein levels. Activin A-induced migration of L929 cells was attenuated by ERK inhibitor FR180204. To conclude, these data indicated that activin A as a novel chemokine induced the chemotactic migration of L929 cells via ERK signaling and possessed the pro-fibrosis role. These findings provide a new insight into understanding of activin A in tissue fibrosis.
Spatiotemporal Analysis of B Cell- and Antibody Secreting Cell-Subsets in Human Melanoma Reveals Metastasis-, Tumor Stage-, and Age-Associated Dynamics
Authors: Chen Minyi , Werner Franziska , Wagner Christine , Simon Martin , Richtig Erika , Mertz Kirsten D. , Griss Johannes , Wagner Stephan N.
Published: May 2021

Background: The role of tumor-associated B cells in human cancer is only starting to emerge. B cells typically undergo a series of developmental changes in phenotype and function, however, data on the composition of the B cell population in human melanoma are largely absent including changes during tumor progression and their potential clinical significance.

Methods: In this study, we compared the number and distribution of six major B cell and antibody secreting cell subpopulations outside tertiary lymphoid structures in whole tumor sections of 154 human cutaneous melanoma samples (53 primary tumors without subsequent metastasis, 44 primary tumors with metastasis, 57 metastatic samples) obtained by seven color multiplex immunohistochemistry and automated tissue imaging and analysis.

Results: In primary melanomas, we observed the highest numbers for plasmablast-like, memory-like, and activated B cell subtypes. These cells showed a patchy, predominant paratumoral distribution at the invasive tumor-stroma margin. Plasma cell-like cells were hardly detected, germinal center- and transitional/regulatory-like B cells not at all. Of the major clinicopathologic prognostic factors for primary melanomas, metastasis was associated with decreased memory-like B cell numbers and a higher age associated with higher plasmablast-like cell numbers. When we compared the composition of B cell subpopulations in primary melanomas and metastatic samples, we found a significantly higher proportion of plasma cell-like cells at distant metastatic sites and a higher proportion of memory-like B cells at locoregional than distant metastatic sites. Both cell types were detected mainly in the para- and intratumoral stroma.

Conclusion: These data provide a first comprehensive and comparative spatiotemporal analysis of major B cell and antibody secreting cell subpopulations in human melanoma and describe metastasis-, tumor stage-, and age-associated dynamics, an important premise for B cell-related biomarker and therapy studies.
Computational Insights Into the Influence of Substitution Groups on the Inclusion Complexation of β-Cyclodextrin
Authors: Yan Xianghua , Wang Yue , Meng Tong , Yan Hui
Published: May 2021

Cyclodextrins (CDs) and their derivatives have good prospects in soil remediation application due to their ability to enhance the stability and solubility of low water-soluble compounds by inclusion performance. To investigate the effect of different structural properties of cyclodextrin and its derivatives on the inclusion complexation, molecular dynamic (MD) simulations were performed on the inclusion complexes formed by three kinds of CDs with polycyclic aromatic hydrocarbons (PAHs). Based on neutral β-CD, the other two CDs were modified by introducing substitutional groups, including 2-hydroxypropyl and sulfonated butyl (SBE) functional groups in the ring structure, called HP-CD and SBE-CD. MD results show that PAH can merely enter into the cavity of SBE–β-CD from its wide rim. The substitutional groups significantly affect the structure of CDs, which may also cause the flipping of the glucose units. However, the substitutional groups can also enlarge the volume of the hydrophobic cavity, resulting in a tight combination with the guest molecules.
Knockdown of lncRNA ENST00000609755.1 Confers Protection Against Early oxLDL-Induced Coronary Heart Disease
Authors: Sun Yi , Huang Shuna , Wan Chunyu , Ruan Qishuang , Xie Xiaoxu , Wei Donghong , Li Guobo , Lin Shaowei , Li Huangyuan , Wu Siying
Published: May 2021

Background: This study investigated the association between long non-coding RNAs (lncRNAs) and coronary heart disease (CHD) and further elucidated the potential biological roles of lncRNAs in CHD pathogenesis.

Methods: A case-control study (590 patients and 590 controls) was conducted from February 2017 and March 2019 in Fuzhou, China. Environmental factors were investigated using questionnaires and physical examinations. Five representative lncRNAs were screened using lncRNA microarray (peripheral blood in 5 cases and 5 controls) and further verified by quantitative real-time polymerase chain reaction (peripheral blood leukocyte in 100 cases and 100 controls). Oxidized low-density lipoprotein (oxLDL) was used to induce a human coronary artery endothelial cell (HCAECs) injury model, and loss of function was used to elucidate the role of lncRNA ENST00000609755.1 (lnc-MICALL2-2) in oxLDL-induced HCAECs injury.

Results: A total of 320 lncRNAs were found dysregulated in CHD patients (fold change> 2, p < 0.05). The results of a discovery microarray, population verification and HCAEC experiments suggested the lnc-MICALL2-2 is upregulated in CHD subjects and in an oxLDL-induced HCAECs injury model. Conversely, lnc-MICALL2-2 inhibition in vitro attenuated the effects of oxLDL on HCAECs morphology, proliferation, and apoptosis.

Conclusion: Elevated expression of lnc-MICALL2-2 is an independent risk factor for CHD, and knockdown subsequently confers protection against early pathological processes of oxLDL-induced CHD.
Prognostic Model to Predict Postoperative Adverse Events in Pediatric Patients With Aortic Coarctation
Authors: Gu Yan , Li Qianqian , Lin Rui , Jiang Wenxi , Wang Xue , Zhou Gengxu , Su Junwu , Fan Xiangming , Gao Pei , Jin Mei , Wang Yuan , Du Jie
Published: May 2021

Background: Postoperative adverse events remain excessively high in surgical patients with coarctation of aorta (CoA). Currently, there is no generally accepted strategy to predict these patients' individual outcomes.

Objective: This study aimed to develop a risk model for the prediction of postoperative risk in pediatric patients with CoA.

Methods: In total, 514 patients with CoA at two centers were enrolled. Using daily clinical practice data, we developed a model to predict 30-day or in-hospital adverse events after the operation. The least absolute shrinkage and selection operator approach was applied to select predictor variables and logistic regression was used to develop the model. Model performance was estimated using the receiver-operating characteristic curve, the Hosmer–Lemeshow test and the calibration plot. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) compared with existing risk strategies were assessed.

Results: Postoperative adverse events occurred in 195 (37.9%) patients in the overall population. Nine predictive variables were identified, including incision of left thoracotomy, preoperative ventilation, concomitant ventricular septal defect, preoperative cardiac dysfunction, severe pulmonary hypertension, height, weight-for-age z-score, left ventricular ejection fraction and left ventricular posterior wall thickness. A multivariable logistic model [area under the curve = 0.8195 (95% CI: 0.7514–0.8876)] with adequate calibration was developed. Model performance was significantly improved compared with the existing Aristotle Basic Complexity (ABC) score (NRI = 47.3%, IDI = 11.5%) and the Risk Adjustment for Congenital Heart Surgery (RACHS-1) (NRI = 75.0%, IDI = 14.9%) in the validation set.

Conclusion: Using daily clinical variables, we generated and validated an easy-to-apply postoperative risk model for patients with CoA. This model exhibited a remarkable improvement over the ABC score and the RACHS-1 method.
Investigation of the Molecular Mechanisms by Which Endothelin-3 Stimulates Preadipocyte Growth
Authors: Siao An-Ci , Shih Li-Jane , Lin Yen-Yue , Tsuei Yi-Wei , Kuo Yow-Chii , Ku Hui-Chen , Chuu Chih-Ping , Hsiao Po-Jen , Kao Yung-Hsi
Published: May 2021

Endothelins induce many biological responses, and they are composed of three peptides: ET-1, ET-2, and ET-3. Reports have indicated that ET-1 regulates cell proliferation, adipogenesis, and other cell responses and that ET-3 stimulates the growth of gastrointestinal epithelial cells and melanocytes. However, the signalling pathways of ET3 that mediate the growth of fat cells are still unclear. Using 3T3-L1 white preadipocytes, we found that ET-3 induced increases in both cell number and BrdU incorporation. Pretreatment with an ETAR antagonist (but not an ETBR antagonist) blocked the ET-3-induced increases in both cell number and BrdU incorporation. Additionally, BQ610 suppressed the ET-3-induced increases in phosphorylation of AMPK, c-JUN, and STAT3 proteins, and pretreatment with specific inhibitors of AMPK, JNK/c-JUN, or JAK/STAT3 prevented the ET-3-induced increases in phosphorylation of AMPK, c-JUN, and STAT3, respectively. Neither p38 MAPK inhibitor nor PKC inhibitor altered the effects of ET-3 on cell growth. These data suggest that ET-3 stimulates preadipocyte growth through the ETAR, AMPK, JNK/c-JUN, and STAT3 pathways. Moreover, ET-3 did not alter HIB1B brown preadipocyte and D12 beige preadipocyte growth, suggesting a preadipocyte type-dependent effect. The results of this study may help explain how endothelin mediates fat cell activity and fat cell-associated diseases.
Passive Solar and Conventional Housing Design: A Comparative Study of Daylighting Energy Efficiency Potential
Authors: Overen Ochuko K. , Meyer Edson L. , Makaka Golden
Published: May 2021

The increasing energy consumption and its resultant CO2 emission in the built environment have revolutionized the housing design. Buildings are strategically designed to harness ambient weather factors for indoor space thermal conditioning and lighting. A comparison of the daylighting and potential environmental mitigations due to the lighting energy consumption in a passive solar and the conventional house was the aim of this study. Both houses used as a case study are in Alice, Eastern Cape in South Africa. The indoor illuminance of the homes was monitored using Li-Cor 210R photometric sensors. Between 07 h00 to 16 h30, the passive solar house’s average daylighting was 217 lux and 56 lux in the conventional house on a clear sky. Under the same sky condition, there was 47% lighting energy saving. This reduces the amount of coal usage by 1.97 kg, 3.53 kg of CO2, 14.80 g of NO2, and 4.76 L of water. In contrast, no energy savings were achieved in the conventional home. The equivalent environmental impacts due to 4.20 kg of coal usage were 7.52 kg of CO2, 31.52 g of NO2 emissions, and 10.14 L of water usage. From the findings, daylight harvest through passive solar design shows the potential of energy savings and environmental mitigation measures in the housing sector.
Hybrid Simulation for Large-Scale AC/DC Power System by Serial Interaction Process
Authors: Zhang Song , Li Guoqing , Li Shuguang , Liu Xintong
Published: May 2021

Electromechanical transient (EMT) and transient stability hybrid simulations can make full use of their fast-solving ability and high-precision computing ability to accurately simulate the dynamic characteristics of large-scale AC/DC systems. This paper selects the bus as the hybrid simulation interface bus in the AC system near the DC system, which can effectively improve the simulation accuracy of the AC/DC system interaction. At the interface bus, Norton equivalent and Thevenin equivalent are applied to the EMT simulation side and electromechanical transient simulation side, respectively. The three-phase simulation data and three-sequence component simulation data are extracted respectively, and the serial iteration method is used for hybrid simulation calculation. This paper takes Zhangbei multi terminal AC/DC system as an example, compares the hybrid simulation results with the EMT simulation results, and tries to verify the accuracy and effectiveness of the hybrid simulation method.
Benchmarking Taxonomic and Genetic Diversity After the Fact: Lessons Learned From the Catastrophic 2019–2020 Australian Bushfires
Authors: Catullo Renee A. , Schembri Rhiannon , Tedeschi Leonardo Gonçalves , Eldridge Mark D. B. , Joseph Leo , Moritz Craig C.
Published: May 2021

Environmental catastrophes are increasing in frequency and severity under climate change, and they substantially impact biodiversity. Recovery actions after catastrophes depend on prior benchmarking of biodiversity and that in turn minimally requires critical assessment of taxonomy and species-level diversity. Long-term recovery of species also requires an understanding of within-species diversity. Australia’s 2019–2020 bushfires were unprecedented in their extent and severity and impacted large portions of habitats that are not adapted to fire. Assessments of the fires’ impacts on vertebrates identified 114 species that were a high priority for management. In response, we compiled explicit information on taxonomic diversity and genetic diversity within fire-impacted vertebrates to provide to government agencies undertaking rapid conservation assessments. Here we discuss what we learned from our effort to benchmark pre-fire taxonomic and genetic diversity after the event. We identified a significant number of candidate species (genetic units that may be undescribed species), particularly in frogs and mammals. Reptiles and mammals also had high levels of intraspecific genetic structure relevant to conservation management. The first challenge was making published genetic data fit for purpose because original publications often focussed on a different question and did not provide raw sequence read data. Gaining access to analytical files and compiling appropriate individual metadata was also time-consuming. For many species, significant unpublished data was held by researchers. Identifying which data existed was challenging. For both published and unpublished data, substantial sampling gaps prevented areas of a species’ distribution being assigned to a conservation unit. Summarising sampling gaps across species revealed that many areas were poorly sampled across taxonomic groups. To resolve these issues and prepare responses to future catastrophes, we recommend that researchers embrace open data principles including providing detailed metadata. Governments need to invest in a skilled taxonomic workforce to document and describe biodiversity before an event and to assess its impacts afterward. Natural history collections should also target increasing their DNA collections based on sampling gaps and revise their collection strategies to increasingly take population-scale DNA samples in order to document within-species genetic diversity.
Supporting Wildfire Response During a Pandemic in the United States: the COVID-19 Incident Risk Assessment Tool
Authors: Thompson Matthew P. , Belval Erin J. , Dilliott Jake , Bayham Jude
Published: May 2021

The onset of the global pandemic in 2020 significantly increased the complexity and uncertainty of wildfire incident response in the United States, and there was a clear role for decision support to inform and enhance coordination and communication efforts. Epidemiological modeling suggested the risk of COVID-19 outbreak at a traditional large fire camp could be substantial and supported the broadscale implementation of mitigations, and management of COVID-19 required expanding the response network to interface with entities such as local public health agencies, hospitals, and emergency operations centers. Despite the early issuance of medical and public health guidance to support wildfire management functions under a COVID-19 modified operating posture, an identified gap was a scale- and scope-appropriate tool to support incident-level assessment of COVID-19 risk. Here we review the development and application of a COVID-19 Incident Risk Assessment Tool intended to fill that gap. After prototyping with fire managers and risk practitioners, including early-season use on several incidents, we built an online dashboard that was used operationally throughout the 2020 fire season. We summarize usage statistics, provide some examples of real use on wildfire incidents, and report feedback from users. The tool helped to fill a critical information gap and was intended to support risk-informed decision-making regarding incident logistics, operations, and COVID-19 mitigations.
Whole-Transcriptome Analysis of Yak and Cattle Heart Tissues Reveals Regulatory Pathways Associated With High-Altitude Adaptation
Authors: Wang Hui , Zhong Jincheng , Wang Jikun , Chai Zhixin , Zhang Chengfu , Xin Jinwei , Wang Jiabo , Cai Xin , Wu Zhijuan , Ji Qiumei
Published: May 2021

Background

The yak (Bos grunniens) is an important livestock species that can survive the extremely cold, harsh, and oxygen-poor conditions of the Qinghai-Tibetan Plateau and provide meat, milk, and transportation for the Tibetans living there. However, the regulatory network that drive this hypoxic adaptation remain elusive.

Results

The heart tissues from LeiRoqi (LWQY) yak and their related cattle (Bos Taurus) breeds, which are two native cattle breeds located in high altitude (HAC) and low altitude (LAC) regions, respectively, were collected for RNA sequencing. A total of 178 co-differentially expressed protein-coding transcripts (co-DETs) were discovered in each of the LAC-vs-LWQY and LAC-vs-HAC comparison groups, including NFATC2, NFATC1, ENPP2, ACSL4, BAD, and many other genes whose functions were reported to be associated with the immune-system, endocrine-system, and lipid metabolism. Two and 230 lncRNA transcripts were differentially expressed in the LAC-vs-LWQY and LAC-vs-HAC comparisons’ respectively, but no lncRNA transcripts that were co-differentially expressed. Among the 58 miRNAs that were co-differentially expressed, 18 were up-regulated and 40 were down-regulated. In addition, 640 (501 up-regulated and 139 down-regulated) and 152 (152 up-regulated and one down-regulated) circRNAs showed differential expression in LAC-vs-LWQY and LAC-vs-HAC comparison groups, respectively, and 53 up-regulated co-differentially expressed circRNAs were shared. Multiple co-DETs, which are the targets of miRNAs/lncRNAs, are significantly enriched in high-altitude adaptation related processes, such as, T cell receptor signaling, VEGF signaling, and cAMP signaling. A competing endogenous RNA (ceRNA) network was constructed by integrating the competing relationships among co-differentially expressed mRNAs, miRNAs, lncRNAs and circRNAs. Furthermore, the hypoxic adaptation related ceRNA network was constructed, and the six mRNAs (MAPKAPK3, PXN, NFATC2, ATP7A, DIAPH1, and F2R), the eight miRNAs (including miR-195), and 15 circRNAs (including novel-circ-017096 and novel-circ-018073) are proposed as novel and promising candidates for regulation of hypoxic adaptation in the heart.

Conclusion

In conclusion, the data recorded in the present study provides new insights into the molecular network of high-altitude adaptation along with more detailed information of protein-coding transcripts and non-coding transcripts involved in this physiological process, the detailed mechanisms behind how these transcripts “crosstalk” with each other during the plateau adaptation are worthy of future research efforts.
Behçet’s Disease—Do Microbiomes and Genetics Collaborate in Pathogenesis?
Authors: Mehmood Nafeesa , Low Liying , Wallace Graham R.
Published: May 2021

Behçet’s disease (BD) is a multisystem autoinflammatory condition characterized by mucosal ulceration, breakdown of immune privilege sites and vasculitis. A genetic basis for BD has been described in genome-wide and validation studies. Similarly, dysbiosis of oral and gut microbiomes have been associated with BD. This review will describe links between genetic polymorphisms in genes encoding molecules involved in gut biology and changes seen in microbiome studies. A potential decrease in bacterial species producing short chain fatty acids linked to mutations in genes involved in their production suggests a potential therapy for BD.
Inflammatory Regulation of CNS Barriers After Traumatic Brain Injury: A Tale Directed by Interleukin-1
Authors: Bodnar Colleen N. , Watson James B. , Higgins Emma K. , Quan Ning , Bachstetter Adam D.
Published: May 2021

Several barriers separate the central nervous system (CNS) from the rest of the body. These barriers are essential for regulating the movement of fluid, ions, molecules, and immune cells into and out of the brain parenchyma. Each CNS barrier is unique and highly dynamic. Endothelial cells, epithelial cells, pericytes, astrocytes, and other cellular constituents each have intricate functions that are essential to sustain the brain’s health. Along with damaging neurons, a traumatic brain injury (TBI) also directly insults the CNS barrier-forming cells. Disruption to the barriers first occurs by physical damage to the cells, called the primary injury. Subsequently, during the secondary injury cascade, a further array of molecular and biochemical changes occurs at the barriers. These changes are focused on rebuilding and remodeling, as well as movement of immune cells and waste into and out of the brain. Secondary injury cascades further damage the CNS barriers. Inflammation is central to healthy remodeling of CNS barriers. However, inflammation, as a secondary pathology, also plays a role in the chronic disruption of the barriers’ functions after TBI. The goal of this paper is to review the different barriers of the brain, including (1) the blood-brain barrier, (2) the blood-cerebrospinal fluid barrier, (3) the meningeal barrier, (4) the blood-retina barrier, and (5) the brain-lesion border. We then detail the changes at these barriers due to both primary and secondary injury following TBI and indicate areas open for future research and discoveries. Finally, we describe the unique function of the pro-inflammatory cytokine interleukin-1 as a central actor in the inflammatory regulation of CNS barrier function and dysfunction after a TBI.
Understanding Immune Responses to Surgical Transplant Procedures in Stevens Johnsons Syndrome Patients
Authors: Soifer Matias , Mousa Hazem M. , Levy Robert B. , Perez Victor L.
Published: May 2021

Stevens Johnsons syndrome (SJS) is a mucocutaneous disorder caused by an autoimmune response most commonly to medications. Unless it is properly managed in the acute setting, this entity can affect the ocular surface causing chronic cicatrizing conjunctivitis with limbal stem cell deficiency and lid anomalies which ultimately result in corneal opacities that may limit patients' visual acuity. When this stage is reached, some patients might need to undergo some form of corneal and/or limbal stem cell transplantation that exposes an already sensitized immune system to a new alloantigen. While the innate immunity plays a role in corneal graft survival, adaptive immune responses play a major part in corneal graft rejection and failure, namely through CD4+ T cell lymphocytes. Hence, the management of the immune response to surgical transplant procedures in SJS patients, involves a dual approach that modulates the inflammatory response to a new alloantigen in the context of an autoimmune sensitized patient. This review will explore and discuss current perspectives and future directions in the field of ocular immunology on how to manage SJS immune responses to ocular surgical procedures, reviewing systemic and local immunosuppressive therapies and protocols to adequately manage this debilitating condition.
Frequency of Positive Conversion of Interferon-Gamma Release Assay Results Among Patients With Inflammatory Bowel Disease Treated With Non-tumor Necrosis Factor Inhibitors
Authors: Kim Kyuwon , Jo Kyung-Wook , Shim Tae Sun , Park Jin Hwa , Hwang Sung Wook , Park Sang Hyoung , Yang Dong-Hoon , Byeon Jeong-Sik , Myung Seung-Jae , Yang Suk-Kyun , Ye Byong Duk
Published: May 2021

Considering the risk of reactivation of latent tuberculosis infection (LTBI), not only before starting tumor necrosis factor inhibitors but also before non-TNF inhibitor therapy, LTBI screening is routinely recommended for patients with inflammatory bowel disease (IBD). However, data on the positive conversion of LTBI test results during non-TNF inhibitor therapy are scarce. Among IBD patients treated with vedolizumab and/or ustekinumab, a total of 91 patients who had negative baseline interferon-gamma release assay (IGRA) results, assessed by QuantiFERON®-TB Gold In-tube or QuantiFERON®-TB Gold Plus, were enrolled. Serial LTBI test results after starting non-TNF inhibitor therapy were collected, and patients' clinical characteristics were analyzed. Positive IGRA conversion was observed in six of 91 patients (6.6%). The cumulative IGRA conversion–free survival rates after starting therapy were 97.7% after 1 year and 86.7% after 2 years. Ulcerative colitis was more common among converters compared with non-converters (66.7 vs. 23.5%, P = 0.040). Among six converters, four had been treated with vedolizumab, one with ustekinumab, and the other with vedolizumab followed by ustekinumab. All six patients had been previously exposed to TNF inhibitors before non-TNF inhibitor therapy: five to infliximab and one to both infliximab and adalimumab. After positive IGRA conversion, none of the six converters developed active tuberculosis while maintaining non-TNF inhibitor therapy (median 6.8 months, range 0.4–32.1 months). Positive IGRA conversion among IBD patients treated with vedolizumab and/or ustekinumab appears to occur somewhat frequently, but its clinical implications remain to be elucidated.
Exploring Multiple Aspects of Taxonomic and Functional Diversity in Microphytobenthic Communities: Effects of Environmental Gradients and Temporal Changes
Authors: Teittinen Anette , Virta Leena
Published: May 2021

Biodiversity has traditionally been quantified using taxonomic information but the importance of also considering its functional characteristics has recently gained an increasing attention among microorganisms. However, studies exploring multiple aspects of taxonomic and functional diversity and their temporal variations are scarce for diatoms, which is one of the most important microbial groups in aquatic ecosystems. Here, our aim was to examine the taxonomic and functional alpha and beta diversities of diatoms in a coastal rock pool system characterized by a naturally high environmental heterogeneity. We also investigated the temporal differences in the diversity patterns and drivers. The relationship between the species richness and functional dispersion was temporally coherent, such that species-poor communities tended to be functionally clustered. The trend between the species richness and taxonomic uniqueness of community composition was temporally inconsistent, changing from negative to non-significant over time. Conductivity or distance to the sea or both were key determinants of species richness, functional dispersion, and uniqueness of community composition. The increase of community dissimilarity with an increasing environmental distance was stronger for the taxonomic than the functional composition. Our results suggest that even minor decreases in the species richness may result in a lowered functional diversity and decreased ecosystem functioning. Species-poor ecosystems may, however, have unique species compositions and high contributions to regional biodiversity. Despite changing the species compositions along the environmental gradients, communities may remain to have a high functional similarity and robustness in the face of environmental changes. Our results highlight the advantage of considering multiple biodiversity metrics and incorporating a temporal component for a deeper understanding of the effects of environmental changes on microbial biodiversity.
Identifying Genes Devoted to the Cell Death Process in the Gene Regulatory Network of Ustilago maydis
Authors: Soberanes-Gutiérrez Cinthia V. , Pérez-Rueda Ernesto , Ruíz-Herrera José , Galán-Vásquez Edgardo
Published: May 2021

Cell death is a process that can be divided into three morphological patterns: apoptosis, autophagy and necrosis. In fungi, cell death is induced in response to intracellular and extracellular perturbations, such as plant defense molecules, toxins and fungicides, among others. Ustilago maydis is a dimorphic fungus used as a model for pathogenic fungi of animals, including humans, and plants. Here, we reconstructed the transcriptional regulatory network of U. maydis, through homology inferences by using as templates the well-known gene regulatory networks (GRNs) of Saccharomyces cerevisiae, Aspergillus nidulans and Neurospora crassa. Based on this GRN, we identified transcription factors (TFs) as hubs and functional modules and calculated diverse topological metrics. In addition, we analyzed exhaustively the module related to cell death, with 60 TFs and 108 genes, where diverse cell proliferation, mating-type switching and meiosis, among other functions, were identified. To determine the role of some of these genes, we selected a set of 11 genes for expression analysis by qRT-PCR (sin3, rlm1, aif1, tdh3 [isoform A], tdh3 [isoform B], ald4, mca1, nuc1, tor1, ras1, and atg8) whose homologues in other fungi have been described as central in cell death. These genes were identified as downregulated at 72 h, in agreement with the beginning of the cell death process. Our results can serve as the basis for the study of transcriptional regulation, not only of the cell death process but also of all the cellular processes of U. maydis.
Serum Metabolite Biomarkers Predictive of Response to PD-1 Blockade Therapy in Non-Small Cell Lung Cancer
Authors: Nie Xiaoqun , Xia Liliang , Gao Fang , Liu Lixia , Yang Yi , Chen Yingying , Duan Huangqi , Yao Yaxian , Chen Zhiwei , Lu Shun , Wang Ying , Yang Chen
Published: May 2021

Background: Despite remarkable success of immunotherapies with checkpoint blockade antibodies targeting programmed cell death protein 1 (PD-1), the majority of patients with non-small-cell lung cancer (NSCLC) have yet to receive durable benefits. We used the metabolomic profiling of early on-treatment serum to explore predictors of clinical outcomes of anti-PD-1 treatment in patients with advanced NSCLC.

Methods: We recruited 74 Chinese patients who had stage IIIB/IV NSCLC-proven tumor progression and were treated with PD-1 inhibitor. The study was comprised of a discovery cohort of patients treated with nivolumab and two validation cohorts of patients receiving tislelizumab or nivolumab. Serum samples were collected 2–3 weeks after the first infusion of PD-1 inhibitor. Metabolomic profiling of serum was performed using ultrahigh performance lipid chromatograph-mass spectrometry. The serum metabolite biomarkers were identified using an integral workflow of nontargeted metabolomic data analysis.

Results: A serum metabolite panel consisting of hypoxanthine and histidine was identified and validated as a predictor of response to PD-1 blockade treatment in patients with advanced NSCLC. High levels of both hypoxanthine and histidine in early on-treatment serum were associated with improved progression-free survival [hazard ratio (HR) = 0.078, 95% confidence interval (CI), 0.027–0.221, p < 0.001] and overall survival (HR = 0.124, 95% CI, 0.039–0.397, p < 0.001) in the discovery cohort. The serum metabolite panel showed a high sensitivity and specificity in distinguishing responders and non-responders in the validation cohorts 1 and 2, with an area under the receiver-operating characteristic curve of 0.933 and 1.000, respectively. High levels of serum hypoxanthine and histidine were correlated with improved progression-free survival in the validation cohort 1 (HR = 0.137, 95% CI, 0.040–0.467, p = 0.001) and in the validation cohort 2 (HR = 0.084, 95% CI, 0.009–0.762, p = 0.028).

Conclusion: Our results revealed that hypoxanthine and histidine in early on-treatment serum are predictive biomarkers of response to PD-1 blockade therapy in patients with advanced NSCLC. The serum biomarker panel would enable early identification of NSCLC patients who may benefit from PD-1 blockade therapy.
Vestibular Function After Cochlear Implantation in Partial Deafness Treatment
Authors: Sosna-Duranowska Magdalena , Tacikowska Grazyna , Gos Elzbieta , Krupa Anna , Skarzynski Piotr Henryk , Skarzynski Henryk
Published: May 2021

Introduction: Cochlear implantation is a fully accepted method of treating individuals with profound hearing loss. Since the indications for cochlear implantation have broadened and include patients with low-frequency residual hearing, single-sided deafness, or an already implanted ear (meaning bilateral cochlear implantation), the emphasis now needs to be on vestibular protection.

Materials and Methods: The research group was made up of 107 patients operated on in the otorhinolaryngosurgery department: 59 females and 48 males, aged 10.4–80.2 years (M = 44.4; SD = 18.4) with hearing loss lasting from 1.4 to 56 years (M = 22.7; SD = 13.5). The patients underwent cVEMP, oVEMP, a caloric test, and vHIT assessment preoperatively, and, postoperatively, cVEMP and oVEMP at 1–3 months and a caloric test and vHIT at 4–6 months.

Results: After cochlear implantation, there was postoperative loss of cVEMP in 19.2% of the patients, oVEMP in 17.4%, reduction of caloric response in 11.6%, and postoperative destruction of the lateral, anterior, and posterior semicircular canal as measured with vHIT in 7.1, 3.9, and 4% respectively.

Conclusions: Hearing preservation techniques in cochlear implantation are connected with vestibular protection, but the risk of vestibular damage in never totally eliminated. The vestibular preservation is associated with hearing preservation and the relation is statistically significant. Informed consent for cochlear implantation must include information about possible vestibular damage. Since the risk of vestibular damage is appreciable, preoperative otoneurological diagnostics need to be conducted in the following situations: qualification for a second implant, after otosurgery (especially if the opposite ear is to be implanted), having a history of vestibular complaints, and when there are no strict audiological or anatomical indications on which side to operate.
The Synergistic Effects of Pyrotinib Combined With Adriamycin on HER2-Positive Breast Cancer
Authors: Wang Chaokun , Deng Shuzhen , Chen Jing , Xu Xiangyun , Hu Xiaochen , Kong Dejiu , Liang Gaofeng , Yuan Xiang , Li Yuanpei , Wang Xinshuai
Published: May 2021

Pyrotinib (PYR) is a pan-HER kinase inhibitor that inhibits signaling via the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. In this study, we aimed to investigate the antitumor efficacy of pyrotinib combined with adriamycin (ADM) and explore its mechanisms on HER2+ breast cancer. We investigated the effects of PYR and ADM on breast cancer in vitro and in vivo. MTT assay, Wound-healing, and transwell invasion assays were used to determine the effects of PYR, ADM or PYR combined with ADM on cell proliferation, migration, and invasion of SK-BR-3 and AU565 cells in vitro. Cell apoptosis and cycle were detected through flow cytometry. In vivo, xenograft models were established to test the effect of PYR, ADM, or the combined therapy on the nude mice. Western blotting was performed to assess the expression of Akt, p-Akt, p-65, p-p65, and FOXC1. The results indicated that PYR and ADM significantly inhibited the proliferation, migration, and invasion of SK-BR-3 and AU565 cells, and the inhibitory rate of the combination group was higher than each monotherapy group. PYR induced G1 phase cell-cycle arrest, while ADM induced G2 phase arrest, while the combination group induced G2 phase arrest. The combined treatment showed synergistic anticancer activities. Moreover, PYR significantly downregulated the expression of p-Akt, p-p65, and FOXC1. In clinical settings, PYR also exerts satisfactory efficacy against breast cancer. These findings suggest that the combination of PYR and ADM shows synergistic effects both in vitro and in vivo. PYR suppresses the proliferation, migration, and invasion of breast cancers through down-regulation of the Akt/p65/FOXC1 pathway.
Feasibility of Different Tumor Delineation Approaches for 18F-PSMA-1007 PET/CT Imaging in Prostate Cancer Patients
Authors: Mittlmeier Lena M. , Brendel Matthias , Beyer Leonie , Albert Nathalie L. , Todica Andrei , Zacherl Mathias J. , Wenter Vera , Herlemann Annika , Kretschmer Alexander , Ledderose Stephan T. , Schmidt-Hegemann Nina-Sophie , Kunz Wolfgang G. , Ricke Jens , Bartenstein Peter , Ilhan Harun , Unterrainer Marcus
Published: May 2021

Background

Delineation of PSMA-positive tumor volume on PET using PSMA-ligands is of highest clinical interest as changes of PSMA-PET/CT-derived whole tumor volume (WTV) have shown to correlate with treatment response in metastatic prostate cancer patients. So far, WTV estimation was performed on PET using 68Ga-labeled ligands; nonetheless, 18F-labeled PET ligands are gaining increasing importance due to advantages over 68Ga-labeled compounds. However, standardized tumor delineation methods for 18F-labeled PET ligands have not been established so far. As correlation of PET-based information and morphological extent in osseous and visceral metastases is hampered by morphological delineation, low contrast in liver tissue and movement artefacts, we correlated CT-based volume of lymph node metastases (LNM) and different PET-based delineation approaches for thresholding on 18F-PSMA-1007 PET.

Methods

Fifty patients with metastatic prostate cancer, 18F-PSMA-1007 PET/CT and non-bulky LNM (short-axis diameter ≥10mm) were included. Fifty LNM were volumetrically assessed on contrast-enhanced CT (volumetric reference standard). Different approaches for tumor volume delineation were applied and correlated with the reference standard: I) fixed SUV threshold, II) isocontour thresholding relative to SUVmax (SUV%), and thresholds relative to III) liver (SUVliver), IV) parotis (SUVparotis) and V) spleen (SUVspleen).

Results

A fixed SUV of 4.0 (r=0.807, r2 = 0.651, p<0.001) showed the best overall association with the volumetric reference. 55% SUVmax (r=0.627, r2 = 0.393, p<0.001) showed highest association using an isocontour-based threshold. Best background-based approaches were 60% SUVliver (r=0.715, r2 = 0.511, p<0.001), 80% SUVparotis (r=0.762, r2 = 0.581, p<0.001) and 60% SUVspleen (r=0.645, r2 = 0.416, p<0.001). Background tissues SUVliver, SUVparotis & SUVspleen did not correlate (p>0.05 each). Recently reported cut-offs for intraprostatic tumor delineation (isocontour 44% SUVmax, 42% SUVmax and 20% SUVmax) revealed inferior association for LNM delineation.

Conclusions

A threshold of SUV 4.0 for tumor delineation showed highest association with volumetric reference standard irrespective of potential changes in PSMA-avidity of background tissues (e. g. parotis). This approach is easily applicable in clinical routine without specific software requirements. Further studies applying this approach for total tumor volume delineation are initiated.
A Long Noncoding RNA, GAS5 Can Be a Biomarker for Docetaxel Response in Castration Resistant Prostate Cancer
Authors: Shan Yuting , Huang Yingbo , Lee Adam M. , Mentzer Joshua , Ling Alexander , Huang R. Stephanie
Published: May 2021

While functional studies of long noncoding RNAs (lncRNAs) have mostly focused on how they influence disease diagnosis and prognosis, the pharmacogenomic relevance of lncRNAs remains largely unknown. Here, we test the hypothesis that the expression of a lncRNA, grow arrest-specific 5 (GAS5) can be a biomarker for docetaxel response in castration resistant prostate cancer (CRPC) using both prostate cancer (PCa) cell lines and CRPC patient datasets. Our results suggest that lower GAS5 expression is associated with docetaxel resistance in both PCa cell lines and CRPC patients. Further experiments also suggest that GAS5 is downregulated in docetaxel resistant CRPC cell lines, which reinforces its potential as a biomarker for docetaxel response. To examine the underlying biological mechanisms, we transiently knockdown GAS5 expression in PCa cell lines and then subject the cells to docetaxel treatment overtime. We did not observe a decrease in docetaxel induced growth inhibition or apoptosis in the siRNA treated cells. The findings suggest that there is no direct causal relationship between change in GAS5 expression and docetaxel response. Subsequently, we explored the indirect regulation among GAS5, ATP binding cassette subfamily B member 1 (ABCB1), and docetaxel sensitivity. We showed that transient knockdown GAS5 did not lead to significant changes in ABCB1 expression. Therefore, we rule out the hypothesis that GAS5 directly down regulate ABCB1 that lead to docetaxel sensitivity. In conclusion, our work suggests that GAS5 can serve as a predictive biomarker for docetaxel response in CRPC; however, the exact mechanism behind the observed correlation remain to be elucidated.
Development and Interpretation of a Genomic Instability Derived lncRNAs Based Risk Signature as a Predictor of Prognosis for Clear Cell Renal Cell Carcinoma Patients
Authors: Yang Huiying , Xiong Xiaoling , Li Hua
Published: May 2021

Background

Clear cell renal cell carcinoma (ccRCC) is a kind of frequently diagnosed cancer, leading to high death rate in patients. Genomic instability (GI) is regarded as playing indispensable roles in tumorigenesis and impacting the prognosis of patients. The aberrant regulation of long non-coding RNAs (lncRNAs) is a main cause of GI. We combined the somatic mutation profiles and expression profiles to identify GI derived lncRNAs (GID-lncRNAs) in ccRCC and developed a GID-lncRNAs based risk signature for prognosis prediction and medication guidance.

Methods

We decided cases with top 25% cumulative number of somatic mutations as genomically unstable (GU) group and last 25% as genomically stable (GS) group, and identified differentially expressed lncRNAs (GID-lncRNAs) between two groups. Then we developed the risk signature with all overall survival related GID-lncRNAs with least absolute shrinkage and selection operator (LASSO) Cox regression. The functions of the GID-lncRNAs were partly interpreted by enrichment analysis. We finally validated the effectiveness of the risk signature in prognosis prediction and medication guidance.

Results

We developed a seven-lncRNAs (LINC00460, AL139351.1, AC156455.1, AL035446.1, LINC02471, AC022509.2, and LINC01606) risk signature and divided all samples into high-risk and low-risk groups. Patients in high-risk group were in more severe clinicopathologic status (higher tumor grade, pathological stage, T stage, and more metastasis) and were deemed to have less survival time and lower survival rate. The efficacy of prognosis prediction was validated by receiver operating characteristic analysis. Enrichment analysis revealed that the lncRNAs in the risk signature mainly participate in regulation of cell cycle, DNA replication, material metabolism, and other vital biological processes in the tumorigenesis of ccRCC. Moreover, the risk signature could help assess the possibility of response to precise treatments.

Conclusion

Our study combined the somatic mutation profiles and the expression profiles of ccRCC for the first time and developed a GID-lncRNAs based risk signature for prognosis predicting and therapeutic scheme deciding. We validated the efficacy of the risk signature and partly interpreted the roles of the seven lncRNAs composing the risk signature in ccRCC. Our study provides novel insights into the roles of genomic instability derived lncRNAs in ccRCC.