bluuebunny/crossref_metadata_2025 huggingface dataset:
Subunit Vaccines Using TLR Triagonist Combination Adjuvants Provide Protection Against Coxiella burnetii While Minimizing Reactogenic Responses
Authors: Fratzke Alycia P. , Jan Sharon , Felgner Jiin , Liang Li , Nakajima Rie , Jasinskas Algis , Manna Saikat , Nihesh Fnu N. , Maiti Sampa , Albin Tyler J. , Esser-Kahn Aaron P. , Davies D. Huw , Samuel James E. , Felgner Philip L. , Gregory Anthony E.
Published: March 2021

Q fever is caused by the obligate intracellular bacterium, Coxiella burnetii, a designated potential agent of bioterrorism because of its route of transmission, resistance to disinfectants, and low infectious dose. The only vaccine licensed for human use is Q-VAX® (Seqirus, licensed in Australia), a formalin-inactivated whole-cell vaccine, which produces severe local and systemic reactogenic responses in previously sensitized individuals. Accordingly, the U.S. Food and Drug Administration and other regulatory bodies around the world, have been reluctant to approve Q-VAX for widespread use. To obviate these adverse reactions, we prepared recombinant protein subunit vaccine candidates containing purified CBU1910, CBU0307, CBU0545, CBU0612, CBU0891, and CBU1398 proteins and TLR triagonist adjuvants. TLR triagonist adjuvants combine different TLR agonists to enhance immune responses to vaccine antigens. We tested both the protective efficacy and reactogenicity of our vaccine candidates in Hartley guinea pigs using intratracheal infection with live C. burnetii. While all of our candidates showed varying degrees of protection during challenge, local reactogenic responses were significantly reduced for one of our vaccine candidates when compared with a formalin-inactivated whole-cell vaccine. Our findings show that subunit vaccines combined with novel TLR triagonist adjuvants can generate protective immunity to C. burnetii infection while reducing reactogenic responses.
Spatiotemporal Dynamics of Maize (Zea mays L.) Root Growth and Its Potential Consequences for the Assembly of the Rhizosphere Microbiota
Authors: Bonkowski Michael , Tarkka Mika , Razavi Bahar S. , Schmidt Hannes , Blagodatskaya Evgenia , Koller Robert , Yu Peng , Knief Claudia , Hochholdinger Frank , Vetterlein Doris
Published: March 2021

Numerous studies have shown that plants selectively recruit microbes from the soil to establish a complex, yet stable and quite predictable microbial community on their roots – their “microbiome.” Microbiome assembly is considered as a key process in the self-organization of root systems. A fundamental question for understanding plant-microbe relationships is where a predictable microbiome is formed along the root axis and through which microbial dynamics the stable formation of a microbiome is challenged. Using maize as a model species for which numerous data on dynamic root traits are available, this mini-review aims to give an integrative overview on the dynamic nature of root growth and its consequences for microbiome assembly based on theoretical considerations from microbial community ecology.
Nasopharyngeal Microbial Communities of Patients Infected With SARS-CoV-2 That Developed COVID-19
Authors: Ventero Maria Paz , Cuadrat Rafael R. C. , Vidal Inmaculada , Andrade Bruno G. N. , Molina-Pardines Carmen , Haro-Moreno Jose M. , Coutinho Felipe H. , Merino Esperanza , Regitano Luciana C. A. , Silveira Cynthia B. , Afli Haithem , López-Pérez Mario , Rodríguez Juan Carlos
Published: March 2021

Background

SARS-CoV-2 is an RNA virus causing COVID-19. The clinical characteristics and epidemiology of COVID-19 have been extensively investigated, however, only one study so far focused on the patient’s nasopharynx microbiota. In this study we investigated the nasopharynx microbial community of patients that developed different severity levels of COVID-19. We performed 16S ribosomal DNA sequencing from nasopharyngeal swab samples obtained from SARS-CoV-2 positive (56) and negative (18) patients in the province of Alicante (Spain) in their first visit to the hospital. Positive SARS-CoV-2 patients were observed and later categorized in mild (symptomatic without hospitalization), moderate (hospitalization), and severe (admission to ICU). We compared the microbiota diversity and OTU composition among severity groups and built bacterial co-abundance networks for each group.

Results

Statistical analysis indicated differences in the nasopharyngeal microbiome of COVID19 patients. 62 OTUs were found exclusively in SARS-CoV-2 positive patients, mostly classified as members of the phylum Bacteroidota (18) and Firmicutes (25). OTUs classified as Prevotella were found to be significantly more abundant in patients that developed more severe COVID-19. Furthermore, co-abundance analysis indicated a loss of network complexity among samples from patients that later developed more severe symptoms.

Conclusion

Our study shows that the nasopharyngeal microbiome of COVID-19 patients showed differences in the composition of specific OTUs and complexity of co-abundance networks. Taxa with differential abundances among groups could serve as biomarkers for COVID-19 severity. Nevertheless, further studies with larger sample sizes should be conducted to validate these results.
Specific Microbial Taxa and Functional Capacity Contribute to Chicken Abdominal Fat Deposition
Authors: Xiang Hai , Gan Jiankang , Zeng Daoshu , Li Jing , Yu Hui , Zhao Haiquan , Yang Ying , Tan Shuwen , Li Gen , Luo Chaowei , Xie Zhuojun , Zhao Guiping , Li Hua
Published: March 2021

Genetically selected chickens with better growth and early maturation show an incidental increase in abdominal fat deposition (AFD). Accumulating evidence reveals a strong association between gut microbiota and adiposity. However, studies focusing on the role of gut microbiota in chicken obesity in conventional breeds are limited. Therefore, 400 random broilers with different levels of AFD were used to investigate the gut microbial taxa related to AFD by 16S rRNA gene sequencing of 76 representative samples, and to identify the specific microbial taxa contributing to fat-related metabolism using shotgun metagenomic analyses of eight high and low AFD chickens. The results demonstrated that the richness and diversity of the gut microbiota decrease as the accumulation of chicken abdominal fat increases. The decrease of Bacteroidetes and the increase of Firmicutes were correlated with the accumulation of chicken AFD. The Bacteroidetes phylum, including the genera Bacteroides, Parabacteroides, and the species, B. salanitronis, B. fragilis, and P. distasonis, were correlated to alleviate obesity by producing secondary metabolites. Several genera of Firmicutes phylum with circulating lipoprotein lipase activity were linked to the accumulation of chicken body fat. Moreover, the genera, Olsenella and Slackia, might positively contribute to fat and energy metabolism, whereas the genus, Methanobrevibacter, was possible to enhance energy capture, and associated to accumulate chicken AFD. These findings provide insights into the roles of the gut microbiota in complex traits and contribute to the development of effective therapies for the reduction of chicken fat accumulation.
Effects of in situ Remediation With Nanoscale Zero Valence Iron on the Physicochemical Conditions and Bacterial Communities of Groundwater Contaminated With Arsenic
Authors: Castaño Ana , Prosenkov Alexander , Baragaño Diego , Otaegui Nerea , Sastre Herminio , Rodríguez-Valdés Eduardo , Gallego José Luis R. , Peláez Ana Isabel
Published: March 2021

Nanoscale Zero-Valent Iron (nZVI) is a cost-effective nanomaterial that is widely used to remove a broad range of metal(loid)s and organic contaminants from soil and groundwater. In some cases, this material alters the taxonomic and functional composition of the bacterial communities present in these matrices; however, there is no conclusive data that can be generalized to all scenarios. Here we studied the effect of nZVI application in situ on groundwater from the site of an abandoned fertilizer factory in Asturias, Spain, mainly polluted with arsenic (As). The geochemical characteristics of the water correspond to a microaerophilic and oligotrophic environment. Physico-chemical and microbiological (cultured and total bacterial diversity) parameters were monitored before and after nZVI application over six months. nZVI treatment led to a marked increase in Fe(II) concentration and a notable fall in the oxidation-reduction potential during the first month of treatment. A substantial decrease in the concentration of As during the first days of treatment was observed, although strong fluctuations were subsequently detected in most of the wells throughout the six-month experiment. The possible toxic effects of nZVI on groundwater bacteria could not be clearly determined from direct observation of those bacteria after staining with viability dyes. The number of cultured bacteria increased during the first two weeks of the treatment, although this was followed by a continuous decrease for the following two weeks, reaching levels moderately below the initial number at the end of sampling, and by changes in their taxonomic composition. Most bacteria were tolerant to high As(V) concentrations and showed the presence of diverse As resistance genes. A more complete study of the structure and diversity of the bacterial community in the groundwater using automated ribosomal intergenic spacer analysis (ARISA) and sequencing of the 16S rRNA amplicons by Illumina confirmed significant alterations in its composition, with a reduction in richness and diversity (the latter evidenced by Illumina data) after treatment with nZVI. The anaerobic conditions stimulated by treatment favored the development of sulfate-reducing bacteria, thereby opening up the possibility to achieve more efficient removal of As.
Learning From Mistakes: The Role of Phages in Pandemics
Authors: Alsaadi Ahlam , Beamud Beatriz , Easwaran Maheswaran , Abdelrahman Fatma , El-Shibiny Ayman , Alghoribi Majed F. , Domingo-Calap Pilar
Published: March 2021

The misuse of antibiotics is leading to the emergence of multidrug-resistant (MDR) bacteria, and in the absence of available treatments, this has become a major global threat. In the middle of the recent severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic, which has challenged the whole world, the emergence of MDR bacteria is increasing due to prophylactic administration of antibiotics to intensive care unit patients to prevent secondary bacterial infections. This is just an example underscoring the need to seek alternative treatments against MDR bacteria. To this end, phage therapy has been proposed as a promising tool. However, further research in the field is mandatory to assure safety protocols and to develop appropriate regulations for its use in clinics. This requires investing more in such non-conventional or alternative therapeutic approaches, to develop new treatment regimens capable of reducing the emergence of MDR and preventing future global public health concerns that could lead to incalculable human and economic losses.
Interdependent Polar Localization of FlhF and FlhG and Their Importance for Flagellum Formation of Vibrio parahaemolyticus
Authors: Arroyo-Pérez Erick Eligio , Ringgaard Simon
Published: March 2021

Failure of the cell to properly regulate the number and intracellular positioning of their flagella, has detrimental effects on the cells’ swimming ability. The flagellation pattern of numerous bacteria is regulated by the NTPases FlhF and FlhG. In general, FlhG controls the number of flagella produced, whereas FlhF coordinates the position of the flagella. In the human pathogen Vibrio parahaemolyticus, its single flagellum is positioned and formed at the old cell pole. Here, we describe the spatiotemporal localization of FlhF and FlhG in V. parahaemolyticus and their effect on swimming motility. Absence of either FlhF or FlhG caused a significant defect in swimming ability, resulting in absence of flagella in a ΔflhF mutant and an aberrant flagellated phenotype in ΔflhG. Both proteins localized to the cell pole in a cell cycle-dependent manner, but displayed different patterns of localization throughout the cell cycle. FlhF transitioned from a uni- to bi-polar localization, as observed in other polarly flagellated bacteria. Localization of FlhG was strictly dependent on the cell pole-determinant HubP, while polar localization of FlhF was HubP independent. Furthermore, localization of FlhF and FlhG was interdependent and required for each other’s proper intracellular localization and recruitment to the cell pole. In the absence of HubP or FlhF, FlhG forms non-polar foci in the cytoplasm of the cell, suggesting the possibility of a secondary localization site within the cell besides its recruitment to the cell poles.
Palmitoylation as a Key Regulator of Ras Localization and Function
Authors: Busquets-Hernández Carla , Triola Gemma
Published: March 2021

Ras proteins require membrane association for proper function. This process is tightly regulated by reversible palmitoylation that controls not only the distribution over different subcellular compartments but also Ras compartmentalization within membrane subdomains. As a result, there is a growing interest in protein palmitoylation and the enzymes that control this process. In this minireview, we discuss how palmitoylation affects the localization and function of Ras proteins. A better understanding of the regulatory mechanism controlling protein lipidation is expected to provide new insights into the functional role of these modifications and may ultimately lead to the development of novel therapeutic approaches.
Prognostic Value of Various Hemostasis Parameters and Neurophysiological Examinations in Spontaneous Intracerebral Hemorrhage: The IRONHEART Study Protocol
Authors: Árokszállási Tamás , Héja Máté , Bagoly Zsuzsa , Kovács Kitti Bernadett , Orbán-Kálmándi Rita , Sarkady Ferenc , Tóth Judit , Fekete Klára , Fekete István , Csiba László
Published: March 2021

Rationale: Stroke is one of the leading causes of death in all developed countries. In Hungary, more than 10,000 patients die annually due to cerebrovascular diseases according to the WHO Mortality Database. Of these patients, 10–15 % suffer non-traumatic intracerebral hemorrhage (ICH). ICH results in a higher rate of mortality as compared to ischemic stroke and outcomes are difficult to predict. In the IRONHEART study, we aim to test various hemostasis parameters and clinical neurophysiological examinations in evaluating outcome in ICH.

Methods: In this prospective, observational study, we plan to enroll consecutive patients with non-traumatic spontaneous ICH admitted to a single Stroke Center (Department of Neurology, University of Debrecen, Hungary). The protocol of the IRONHEART study includes the investigation of detailed clinical, laboratory investigations, and various neurophysiological examinations. Stroke severity is quantified based on the National Institutes of Health Stroke Scale (NIHSS) on admission and day 7, 14, and 90 after the onset of stroke. Cranial CT is performed on admission, day 14, and 90 to estimate the ICH volume. Modified Rankin Scale (mRS) is used for evaluating the long-term outcome (90 days post-event). Blood is drawn immediately on admission for specific hemostasis tests. Digital and quantitative EEG techniques and motor evoked potential (MEP) are performed to evaluate the prognosis of cerebral hemorrhage on admission (within 24–48 h), immediately before discharge (~10–14 days later), and 3 months after the event.

Outcomes: The following outcomes are investigated: primary outcomes: mortality by day 14 and day 90, secondary long-term outcome at 90 days post-event where mRS 0–2 is defined as favorable long-term outcome.

Discussion: If associations between outcomes and the investigated parameters (hemostasis and neurophysiological examinations) are confirmed, results might aid prognosis assessment in this subtype of stroke with particularly high mortality. Improving clinical grading systems on ICH severity and outcomes by including the investigated parameters could help to better guide the management of these patients in the future.
Illuminating the Brain With X-Rays: Contributions and Future Perspectives of High-Resolution Microtomography to Neuroscience
Authors: Rodrigues Paulla Vieira , Tostes Katiane , Bosque Beatriz Pelegrini , Godoy João Vitor Pereira de , Amorim Neto Dionisio Pedro , Dias Carlos Sato Baraldi , Fonseca Matheus de Castro
Published: March 2021

The assessment of three-dimensional (3D) brain cytoarchitecture at a cellular resolution remains a great challenge in the field of neuroscience and constant development of imaging techniques has become crucial, particularly when it comes to offering direct and clear obtention of data from macro to nano scales. Magnetic resonance imaging (MRI) and electron or optical microscopy, although valuable, still face some issues such as the lack of contrast and extensive sample preparation protocols. In this context, x-ray microtomography (μCT) has become a promising non-destructive tool for imaging a broad range of samples, from dense materials to soft biological specimens. It is a new supplemental method to be explored for deciphering the cytoarchitecture and connectivity of the brain. This review aims to bring together published works using x-ray μCT in neurobiology in order to discuss the achievements made so far and the future of this technique for neuroscience.
The Effect and Possible Mechanism of Intradiscal Injection of Simvastatin in the Treatment of Discogenic Pain in Rats
Authors: Huang Xiaodong , Zheng Changkun , Wang Weiheng , Ye Xiaojian , Lin Chia-Ying , Wu Zenghui
Published: March 2021

To study the effect of intradiscal injection of simvastatin on discogenic pain in rats and its possible mechanism, 30 adult female rats were used in this experiment. Twenty rats were randomly divided into sham operation group (Control group), intervertebral disk degeneration group (DDD group), intervertebral disk degeneration + hydrogel group (DDD + GEL group), and intervertebral disk degeneration + simvastatin group (DDD + SIM group). The mechanical pain threshold and cold sensation in rats were measured. The contents of NF-kappa B1, RelA, GAP43, SP, CGRP, TRPM 8, IL-1β, and TNF-α in the intervertebral disk (IVD), the corresponding contents of dorsal root ganglion (DRG) and plantar skin GAP43 and TRPM 8 were quantitatively detected by PCR. The corresponding IVDs were stained to detect their degeneration. There was no significant difference in the mechanical pain threshold between the groups at each time point. From the first day to the 8th week after surgery, the cold-sensing response of the DDD group was significantly higher than that of the Control group (P < 0.05). At 7 and 8 weeks postoperatively, the cold-sensing response of the DDD + SIM group was significantly lower than that of the DDD + GEL group (P < 0.05). The levels of NF-κB1, RelA, GAP43, SP, CGRP, TRPM8, IL-1β, and TNF-α in the IVD of DDD + SIM group were significantly lower than those in DDD group (P < 0.05). The content of GAP43 and TRPM8 in rat plantar skin decreased significantly and TRPM8 in DRG decreased significantly (P < 0.05).
Gene Therapy to the Retina and the Cochlea
Authors: Crane Ryan , Conley Shannon M. , Al-Ubaidi Muayyad R. , Naash Muna I.
Published: March 2021

Vision and hearing disorders comprise the most common sensory disorders found in people. Many forms of vision and hearing loss are inherited and current treatments only provide patients with temporary or partial relief. As a result, developing genetic therapies for any of the several hundred known causative genes underlying inherited retinal and cochlear disorders has been of great interest. Recent exciting advances in gene therapy have shown promise for the clinical treatment of inherited retinal diseases, and while clinical gene therapies for cochlear disease are not yet available, research in the last several years has resulted in significant advancement in preclinical development for gene delivery to the cochlea. Furthermore, the development of somatic targeted genome editing using CRISPR/Cas9 has brought new possibilities for the treatment of dominant or gain-of-function disease. Here we discuss the current state of gene therapy for inherited diseases of the retina and cochlea with an eye toward areas that still need additional development.
Effect of He Plasma Jet Versus Surface Plasma on the Metabolites of Acute Myeloid Leukemia Cells
Authors: Xu Dehui , Ning Ning , Xu Yujing , Xia Wenjie , Liu Dingxin , Chen Hailan , Kong Michael G.
Published: March 2021

Cold atmospheric plasma, including plasma jet and surface plasma, can promote the apoptosis of cancer cells without causing significant damage to surrounding normal cells, which was hopeful to be applied to the clinical cancer therapy. However, experimental plasma devices used directly to clinical experiments has challenges in technology and methods, especially the difference in killing tumor cells efficiency of these two common plasma sources. Therefore, it is great necessity to explore the differences in treating tumors between different plasma sources. This paper achieved good killing efficiency by using two kinds of cold atmospheric plasma generating devices, namely plasma jet and surface plasma treatment along acute myeloid leukemia (AML). The results showed that the He plasma jet kills leukemia cells more efficiently than surface plasma with the same voltage and frequency and the same time. By GC-TOFMS and metabolomics analysis, this paper compared the differential metabolites of leukemia cells treated by two plasma devices and the key metabolic pathways closely related to differential metabolites. Simultaneously, we found alanine, aspartate and glutamate metabolism was most correlated with a key differential metabolite, glutamine. It was found that the glutaminase activity of He plasma jet group was lower than that of surface plasma group, which might be a reason for He plasma jet group to kill tumor cells better. It was also worth noting that relative quantity of glucose metabolites of plasma jet treatment group was lower than that of surface plasma treatment group. This study provides the basis for clinical trials for future.
In Comparison to PSA, Interim Ga-68-PSMA PET/CT Response Evaluation Based on Modified RECIST 1.1 After 2nd Cycle Is Better Predictor of Overall Survival of Prostate Cancer Patients Treated With 177Lu-PSMA
Authors: Prasad Vikas , Huang Kai , Prasad Sonal , Makowski Marcus R. , Czech Norbert , Brenner Winfried
Published: March 2021

Background

Prostate-specific membrane antigen (PSMA) targeting radioligands have transformed treatment of prostate cancer. Radioligand therapy (RLT) with 177Lu-PSMA in metastasized castration resistant prostate cancer (mCRPC) achieves objective response and disease stabilization in roughly two third of patients, whereas one third of patients progress. This study was performed to assess the role of interim PSMA PET/CT after the 2nd cycle of RLT for early prediction of overall survival in patients undergoing RLT with 177Lu-PSMA.

Methods

38 mCRPC patients (68.9 ± 8.1 y) treated with at least two cycles of RLT at 8 week intervals and interim 68Ga-PSMA PET/CT (PET) at 8–10 weeks after the 2nd cycle of RLT were included in this study. Prostate-specific antigen (PSA) response was evaluated according to the Prostate Cancer Working Group 3 criteria. Radiographic response assessment of soft tissue, lymph node, and bone lesions was performed according to RECIST 1.1 including the PET component. Patients’ data were collected for follow-up from the local Comprehensive Cancer Center Register.

Results

Median follow-up was 19.7 months (4.7–45.3). PSA response after the 2nd therapy cycle showed partial remission (PR) in 23.7%, stable disease (SD) in 50%, and progressive disease (PD) in 26.3% of patients. In comparison, 52.6, 23.7, and 23.7% of patients showed PR, SD, and PD respectively on PET/CT. The strength of agreement between PSA response and PET/CT response criteria was only fair (kappa 0.346). Median overall survival (OS) was 22.5 months (95% CI: 15.8–29.2). Median OS stratified to PSA/PET response was 25.6/25.6 months for PR, 21.7/30.6 months for SD and 19.4/13.1 months for PD (p = 0.496 for PSA and 0.013 for PET/CT response).

Conclusions

Interim PSMA PET/CT based response evaluation at 8–10 weeks after the 2nd cycle of RLT is predictive of overall survival and PD in patients treated with 177Lu-PSMA. On the contrary, PSA appears to have only limited predictive value.
A Voxel-Based Radiographic Analysis Reveals the Biological Character of Proneural-Mesenchymal Transition in Glioblastoma
Authors: Qi Tengfei , Meng Xiangqi , Wang Zhenyu , Wang Xinyu , Sun Nan , Ming Jianguang , Ren Lejia , Jiang Chuanlu , Cai Jinquan
Published: March 2021

Introduction: Proneural and mesenchymal subtypes are the most distinct demarcated categories in classification scheme, and there is often a shift from proneural type to mesenchymal subtype in the progression of glioblastoma (GBM). The molecular characters are determined by specific genomic methods, however, the application of radiography in clinical practice remains to be further studied. Here, we studied the topography features of GBM in proneural subtype, and further demonstrated the survival characteristics and proneural-mesenchymal transition (PMT) progression of samples by combining with the imaging variables.

Methods: Data were acquired from The Cancer Imaging Archive (TCIA, http://cancerimagingarchive.net). The radiography image, clinical variables and transcriptome subtype from 223 samples were used in this study. Proneural and mesenchymal subtype on GBM topography based on overlay and Voxel-based lesion-symptom mapping (VLSM) analysis were revealed. Besides, we carried out the comparison of survival analysis and PMT progression in and outside the VLSM-determined area.

Results: The overlay of total GBM and separated image of proneural and mesenchymal subtype revealed a correlation of the two subtypes. By VLSM analysis, proneural subtype was confirmed to be related to left inferior temporal medulla, and no significant voxel was found for mesenchymal subtype. The subsequent comparison between samples in and outside the VLSM-determined area showed difference in overall survival (OS) time, tumor purity, epithelial-mesenchymal transition (EMT) score and clinical variables.

Conclusions: PMT progression was determined by radiography approach. GBM samples in the VLSM-determined area tended to harbor the signature of proneural subtype. This study provides a valuable VLSM-determined area related to the predilection site, prognosis and PMT progression by the association between GBM topography and molecular characters.
Comprehensive Analysis of the Functions and Prognostic Value of RNA-Binding Proteins in Thyroid Cancer
Authors: Ma Yue , Yin Shi , Liu Xiao-feng , Hu Jing , Cai Ning , Zhang Xiao-bei , Fu Li , Cao Xu-chen , Yu Yue
Published: March 2021

RNA binding proteins (RBPs) have been proved to play pivotal roles in a variety types of tumors. However, there is no convincible evidence disclosing the functions of RBPs in thyroid cancer (THCA) thoroughly and systematically. Integrated analysis of the functional and prognostic effect of RBPs help better understanding tumorigenesis and development in thyroid and may provide a novel therapeutic method for THCA. In this study, we obtained a list of human RBPs from Gerstberger database, which covered 1,542 genes encoding RBPs. Gene expression data of THCA was downloaded from The Cancer Genome Atlas (TCGA, n = 567), from which we extracted 1,491 RBPs’ gene expression data. We analyzed differentially expressed RBPs using R package “limma”. Based on differentially expressed RBPs, we constructed protein-protein interaction network and the GO and KEGG pathway enrichment analyses were carried out. We found six RBPs (AZGP1, IGF2BP2, MEX3A, NUDT16, NUP153, USB1) independently associated with prognosis of patients with thyroid cancer according to univariate and multivariate Cox proportional hazards regression models. The survival analysis and risk score analysis achieved good performances from this six-gene prognostic model. Nomogram was constructed to guide clinical decision in practice. Finally, biological experiments disclosed that NUP153 and USB1 can significantly impact cancer cell proliferation and migration. In conclusion, our research provided a new insight of thyroid tumorigenesis and development based on analyses of RBPs. More importantly, the six-gene model may play an important role in clinical practice in the future.
A Novel c-MET-Targeting Antibody-Drug Conjugate for Pancreatic Cancer
Authors: Jin Yangbing , Zhang Zehui , Zou Siyi , Li Fanlu , Chen Hao , Peng Chenghong , Deng Xiaxing , Wen Chenlei , Shen Baiyong , Zhan Qian
Published: March 2021

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated death in the United States and has a 5-year survival rate of <4%. Although much effort has been invested in the research and development of pancreatic cancer drugs over the past 30 years, due to the lack of effective targetable carcinogenic drivers, no new targeted therapies that can improve patient prognosis have been approved for clinical use. SHR-A1403 is a new c-mesenchymal-epithelial transition factor (c-MET) antibody-drug conjugate that can be used for the targeted treatment of PDAC with high c-MET expression. This study reports for the first time the application prospects of SHR-A1403 in preclinical models of PDAC. SHR-A1403 significantly inhibited the proliferation, migration, and invasion of pancreatic cancer cells and induced cell cycle arrest and apoptosis. These changes were caused by inhibition of intracellular cholesterol biosynthesis by SHR-A1403. Therefore, targeting c-MET through SHR-A1403 showed strong preclinical anti-tumour efficacy in pancreatic cancer. Our work suggests the potential application of c-MET-targeted antibody-drug conjugate treatment for PDAC in clinical practise.
Pretreatment Inflammatory-Nutritional Biomarkers Predict Responses to Neoadjuvant Chemoradiotherapy and Survival in Locally Advanced Rectal Cancer
Authors: Wang Yijun , Chen Lejun , Zhang Biyun , Song Wei , Zhou Guowei , Xie Ling , Yu Dahai
Published: March 2021

Background

To evaluate the value of pretreatment inflammatory-nutritional biomarkers in predicting responses to neoadjuvant chemoradiotherapy (nCRT) and survival in patients with locally advanced rectal cancer (LARC).

Methods

Patients with LARC who underwent nCRT and subsequent surgery between October 2012 and December 2019 were considered for inclusion. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and prognostic nutritional index (PNI) were calculated from according to routine laboratory data within 1 week prior to nCRT. The correlations between baseline inflammatory-nutritional biomarkers and responses were analyzed using Chi-square test or Fisher’s exact test, and multivariate logistic regression analysis was performed to identify the independent predictors of pathological responses to nCRT. Univariate and multivariate Cox proportional hazard models were used to assess the correlations of predictors with disease-free survival (DFS) and overall survival (OS).

Results

A total of 273 patients with LARC were enrolled in this study. Higher LMR and PNI were observed in the good-response group, meanwhile higher NLR and PLR were observed in the poor-response group. Multivariate logistic regression analysis results revealed that PLR and PNI independently predicted responses to nCRT. Multivariable Cox regression analysis determined that PNI was an independent predictor of DFS and OS in patients with LARC. The value of pretreatment PNI in predicting responses and survival was continuously superior to those of NLR, PLR, and LMR. The optimal cutoff value of the PNI was approximate 45. Subgroup analyses indicated that the pathological responses and survival in the high PNI group (≥ 45) were significantly better than those in the low PNI group (< 45), especially in patients with clinical stage III rectal cancer.

Conclusion

The pretreatment PNI can serve as a promising predictor of response to nCRT and survival in patients with LACR, which is superior to NLR, PLR, and LMR, and the patients with clinical stage III rectal cancer who have a higher PNI are more likely to benefit from nCRT.
LncRNA POU3F3 Contributes to Dacarbazine Resistance of Human Melanoma Through the MiR-650/MGMT Axis
Authors: Wu Kai , Wang Qiang , Liu Yu-Lin , Xiang Zhuo , Wang Qing-Qing , Yin Li , Liu Shun-Li
Published: March 2021

Background: Alkylating agents are critical therapeutic options for melanoma, while dacarbazine (DTIC)-based chemotherapy showed poor sensitivity in clinical trials. Long non-coding RNAs (lncRNAs) were highlighted in the progression of malignant tumors in recent years, whereas little was known about their involvement in melanoma.

Methods: The functional role and molecular mechanism of lncRNA POU3F3 were evaluated on DTIC-resistant melanoma cells. Further studies analyzed its clinical role in the disease progression of melanoma.

Results: We observed elevated the expression of lncRNA POU3F3 in the DTIC-resistant melanoma cells. Gain-of-function assays showed that the overexpression of lncRNA POU3F3 maintained cell survival with DTIC treatment, while the knockdown of lncRNA POU3F3 restored cell sensitivity to DTIC. A positive correlation of the expression O6-methylguanine-DNA-methyltransferase (MGMT) was observed with lncRNA POU3F3 in vitro and in vivo. Bioinformatic analyses predicted that miR-650 was involved in the lncRNA POU3F3-regulated MGMT expression. Molecular analysis indicated that lncRNA POU3F3 worked as a competitive endogenous RNA to regulate the levels of miR-650, and the lncRNA POU3F3/miR-650 axis determined the transcription of MGMT in melanoma cells to a greater extent. Further clinical studies supported that lncRNA POU3F3 was a risk factor for the disease progression of melanoma.

Conclusion: LncRNA POU3F3 upregulated the expression of MGMT by sponging miR-650, which is a crucial way for DTIC resistance in melanoma. Our results indicated that lncRNA POU3F3 was a valuable biomarker for the disease progression of melanoma.
Assessment of Efficiency and Safety of Apatinib in Advanced Bone and Soft Tissue Sarcomas: A Systematic Review and Meta-Analysis
Authors: Long Zuoyao , Huang Mengquan , Liu Kaituo , Li Minghui , Li Jing , Zhang Hongmei , Wang Zhen , Lu Yajie
Published: March 2021

Background

Previous studies, both in vitro and in vivo, have established that apatinib has anti-tumor properties. However, insufficient empirical evidence of the efficacy and safety of apatinib has been published for bone and soft tissue sarcoma, the reported results differing widely. Here, we conducted a meta-analysis to assess the efficacy and toxicity of apatinib for the treatment of bone and soft tissue sarcoma.

Methods

Pubmed, Medline, Web of Science, ScienceDirect, Ovid, Embase, Cochrane Library, Scopus, Vip (China), Cnki (China), Wanfang (China), and CBM (China) databases and literature from conferences were searched for studies of apatinib for the treatment of bone and soft tissue sarcomas, published from the inception of each database to Sep 1, 2020, without language restrictions. Primary outcomes were efficacy and toxicity of apatinib for the treatment of bone and soft tissue sarcoma, including treatment response, progression-free survival (PFS), and the incidence of adverse events. After extraction of data and methodological quality evaluation, random or fixed-effects models, as appropriate, were selected to calculate pooled effect estimates using R software (Version 3.4.1).

Results

A total of 21 studies with 827 participants were included in the present meta-analysis. The mean MINORS score was 10.48 ± 1.75 (range: 7-13), indicating evidence of moderate quality. Pooled outcomes indicated that overall response rate (ORR) and disease control rate (DCR) were 23.85% (95% CI: 18.47%-30.21%) and 79.16% (95% CI: 73.78%-83.68%), respectively. Median PFS ranged from 3.5 to 13.1 months, with a mean of 7.08 ± 2.98 months. Furthermore, the rates of PFS (PFR) after 1, 6, and 12 months were 99.31%, 44.90%, and 14.31%, respectively. Drug-related toxicity appears to be common in patients administered apatinib, for which hand-foot syndrome (41.13%), hypertension (36.15%), and fatigue (20.52%) ranked the top three most common adverse events. However, the incidence of grade 3-4 adverse events was relatively low and manageable.

Conclusions

Based on the best evidence currently available, apatinib demonstrates promising clinical efficacy and an acceptable safety profile for the treatment of advanced bone and soft tissue sarcoma, although additional high-quality clinical studies are required to further define its properties and toxicity.
Centella asiatica Extract Attenuates Kidney Fibrosis Through Reducing Mesenchymal Transition and Inflammation in Ureteral Ligation Model in Mice
Authors: Sari Dwi Cahyani Ratna , Budiharjo Santosa , Afifah Husnari , Jasmin Destantry , Kokasih Orisativa , Putri Tiara Gitami , Arifiani Karina , Setyaningsih Wiwit Ananda Wahyu , Arfian Nur
Published: March 2021

Background: Kidney fibrosis is the common final pathway of chronic kidney disease (CKD), and is characterized by inflammation, mesenchymal transition with myofibroblast formation and epithelial to mesenchymal transition (EMT). Centella asiatia (CeA) is an herb that has a reno-protective effect. However, its mechanism of action in kidney fibrosis has not been elucidated.

Aim: To elucidate the effect of CeA in amelioration of kidney fibrosis in a unilateral ureteral obstruction (UUO) model and focus on mesenchymal transition and inflammation.

Methods: Unilateral ureteral obstruction was performed in male Swiss-background mice (age: 2–3 months, weight: 30–40 g, UUO group n = 6) to induce kidney fibrosis. Two doses of CeA extract with oral administration, 210 and 840 mg/kg body weight were added in UUO (U+C210 and U+C840 groups, each n = 6). The sham operation procedure was performed for the control group (SO, n = 6). The mice were euthanized at day-14 after operation. Tubular injury and interstitial fibrosis area fractions in kidney tissues of the mice were quantified based on periodic acid-Schiff (PAS) and Sirius Red (SR) staining. Immunostaining was performed for examination of fibroblast (PDGFR-β), myofibroblast (α-SMA), Monocyte Chemoattractant Protein-1 (MCP-1) and macrophage (CD68), meanwhile double immunofluorescence was performed with PDGFR-β and α-SMA. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to examine mRNA expression of TGF-β, Collagen-1, Snail, E-cadherin, vimentin, fibroblast-specific protein 1 (FSP-1), CD68, toll-like receptor 4 (TLR4), and MCP-1.

Results: We observed a significantly higher interstitial fibrosis area fraction and tubular injury (p < 0.001) with fibroblast expansion and myofibroblast formation in the UUO group than in the SO group. These findings were associated with higher mRNA expression of TGF-β, Collagen-1, Snail, vimentin, FSP-1, CD68, TLR4, and MCP-1 and lower mRNA expression of E-cadherin. The U+C840 group had a significantly lower tubular injury score and interstitial fibrosis area fraction, which associated with downregulation of mRNA expression of TGF-β, Collagen-1, Snail, vimentin, FSP-1, CD68, TLR4, and MCP-1, with upregulation of mRNA expression of E-cadherin. Immunostaining observation revealed the U+C840 group demonstrated reduction of macrophage infiltration and myofibroblast expansion.

Conclusion: CeA treatment with dose-dependently ameliorates mesenchymal transition and inflammation in kidney fibrosis in mice.
Thermodynamic and Mechanical Properties of DMPC/Cholesterol Mixed Monolayers at Physiological Conditions
Authors: Bañuelos-Frias Alan , Castañeda-Montiel Victor Manuel , Alvizo-Paez Edgar Rogelio , Vazquez-Martinez Emmanuel Antonio , Gomez Eduardo , Ruiz-Garcia Jaime
Published: March 2021

One of the main known effects of cholesterol is to rigidify the cell membrane throughout the so-called condensing effect. Although many studies have been done in mixtures of cholesterol with different membrane lipids, there are not many studies in a wide concentration range of cholesterol or at physiological conditions. In this work, we studied mixtures of DMPC/Cholesterol monolayers to determine the effect of cholesterol, from very low to physiological concentrations and two pHs. We use a Langmuir balance and Brewster angle microscopy to study their thermodynamic behavior at 37.0 ± 0.1°C at the air/solution interface. From the analysis of the (π−A) isotherms, we determined the excess area and the compressibility elastic modulus to determine the monolayers mechanical properties. Surprisingly, we found three main effects of cholesterol: The first one is a fluidization effect of the monolayer at all cholesterol concentrations. The second effect is the so-called condensing effect that appears due to the non-ideality of the mixture. The third effect is a stiffness of the monolayer as the cholesterol concentration increases. These effects are stronger in pure water, pH ≈ 6.6, than on buffer at physiological pH = 7.4. We also found that all mixtures are thermodynamically stable at all concentrations at a surface pressure of 30.1 ± 1.6 and 27.4 ± 3.2 mN/m in pure water and buffer, respectively. Furthermore, we compared this stability with a fatty acid monolayer that shows a much lower surface pressure equilibrium value that DMPC or its mixtures with cholesterol, indicating a possibly reason why double chain lipids are better than single chain lipids to made up the cell membrane.
The Anticipation of Gravity in Human Ballistic Movement
Authors: Waldvogel Janice , Ritzmann Ramona , Freyler Kathrin , Helm Michael , Monti Elena , Albracht Kirsten , Stäudle Benjamin , Gollhofer Albert , Narici Marco
Published: March 2021

Stretch-shortening type actions are characterized by lengthening of the pre-activated muscle-tendon unit (MTU) in the eccentric phase immediately followed by muscle shortening. Under 1 g, pre-activity before and muscle activity after ground contact, scale muscle stiffness, which is crucial for the recoil properties of the MTU in the subsequent push-off. This study aimed to examine the neuro-mechanical coupling of the stretch-shortening cycle in response to gravity levels ranging from 0.1 to 2 g. During parabolic flights, 17 subjects performed drop jumps while electromyography (EMG) of the lower limb muscles was combined with ultrasound images of the gastrocnemius medialis, 2D kinematics and kinetics to depict changes in energy management and performance. Neuro-mechanical coupling in 1 g was characterized by high magnitudes of pre-activity and eccentric muscle activity allowing an isometric muscle behavior during ground contact. EMG during pre-activity and the concentric phase systematically increased from 0.1 to 1 g. Below 1 g the EMG in the eccentric phase was diminished, leading to muscle lengthening and reduced MTU stretches. Kinetic energy at take-off and performance were decreased compared to 1 g. Above 1 g, reduced EMG in the eccentric phase was accompanied by large MTU and muscle stretch, increased joint flexion amplitudes, energy loss and reduced performance. The energy outcome function established by linear mixed model reveals that the central nervous system regulates the extensor muscles phase- and load-specifically. In conclusion, neuro-mechanical coupling appears to be optimized in 1 g. Below 1 g, the energy outcome is compromised by reduced muscle stiffness. Above 1 g, loading progressively induces muscle lengthening, thus facilitating energy dissipation.
The Utility of Cerebrovascular Reactivity MRI in Brain Rehabilitation: A Mechanistic Perspective
Authors: Krishnamurthy Venkatagiri , Sprick Justin D. , Krishnamurthy Lisa C. , Barter Jolie D. , Turabi Aaminah , Hajjar Ihab M. , Nocera Joe R.
Published: March 2021

Cerebrovascular control and its integration with other physiological systems play a key role in the effective maintenance of homeostasis in brain functioning. Maintenance, restoration, and promotion of such a balance are one of the paramount goals of brain rehabilitation and intervention programs. Cerebrovascular reactivity (CVR), an index of cerebrovascular reserve, plays an important role in chemo-regulation of cerebral blood flow. Improved vascular reactivity and cerebral blood flow are important factors in brain rehabilitation to facilitate desired cognitive and functional outcomes. It is widely accepted that CVR is impaired in aging, hypertension, and cerebrovascular diseases and possibly in neurodegenerative syndromes. However, a multitude of physiological factors influence CVR, and thus a comprehensive understanding of underlying mechanisms are needed. We are currently underinformed on which rehabilitation method will improve CVR, and how this information can inform on a patient’s prognosis and diagnosis. Implementation of targeted rehabilitation regimes would be the first step to elucidate whether such regimes can modulate CVR and in the process may assist in improving our understanding for the underlying vascular pathophysiology. As such, the high spatial resolution along with whole brain coverage offered by MRI has opened the door to exciting recent developments in CVR MRI. Yet, several challenges currently preclude its potential as an effective diagnostic and prognostic tool in treatment planning and guidance. Understanding these knowledge gaps will ultimately facilitate a deeper understanding for cerebrovascular physiology and its role in brain function and rehabilitation. Based on the lessons learned from our group’s past and ongoing neurorehabilitation studies, we present a systematic review of physiological mechanisms that lead to impaired CVR in aging and disease, and how CVR imaging and its further development in the context of brain rehabilitation can add value to the clinical settings.
β-Hexosaminidases Along the Secretory Pathway of Nicotiana benthamiana Have Distinct Specificities Toward Engineered Helminth N-Glycans on Recombinant Glycoproteins
Authors: Alvisi Nicolò , van Noort Kim , Dwiani Sarlita , Geschiere Nathan , Sukarta Octavina , Varossieau Koen , Nguyen Dieu-Linh , Strasser Richard , Hokke Cornelis H. , Schots Arjen , Wilbers Ruud H. P.
Published: March 2021

Secretions of parasitic worms (helminths) contain a wide collection of immunomodulatory glycoproteins with the potential to treat inflammatory disorders, like autoimmune diseases. Yet, the identification of single molecules that can be developed into novel biopharmaceuticals is hampered by the limited availability of native parasite-derived proteins. Recently, pioneering work has shown that helminth glycoproteins can be produced transiently in Nicotiana benthamiana plants while simultaneously mimicking their native helminth N-glycan composition by co-expression of desired glycosyltransferases. However, efficient “helminthization” of N-glycans in plants by glyco-engineering seems to be hampered by the undesired truncation of complex N-glycans by β-N-acetyl-hexosaminidases, in particular when aiming for the synthesis of N-glycans with antennary GalNAcβ1-4GlcNAc (LacdiNAc or LDN). In this study, we cloned novel β-hexosaminidase open reading frames from N. benthamiana and characterized the biochemical activity of these enzymes. We identified HEXO2 and HEXO3 as enzymes responsible for the cleavage of antennary GalNAc residues of N-glycans on the model helminth glycoprotein kappa-5. Furthermore, we reveal that each member of the HEXO family has a distinct specificity for N-glycan substrates, where HEXO2 has strict β-galactosaminidase activity, whereas HEXO3 cleaves both GlcNAc and GalNAc. The identification of HEXO2 and HEXO3 as major targets for LDN cleavage will enable a targeted genome editing approach to reduce undesired processing of these N-glycans. Effective knockout of these enzymes could allow the production of therapeutically relevant glycoproteins with tailor-made helminth N-glycans in plants.