bluuebunny/crossref_metadata_2025 huggingface dataset:
Kahoot, is it fun or unfun? Gamifying vocabulary learning to boost exam scores, engagement, and motivation
Authors: Rojabi Ahmad Ridho , Setiawan Slamet , Munir Ahmad , Purwati Oikurema , Safriyani Rizka , Hayuningtyas Nina , Khodijah Siti , Amumpuni Rengganis Siwi
Published: September 2022

In language learning environments, technology is rapidly manipulated to encourage engagement, promote autonomy, and boost motivation. Many instructors have initiated to exploit online platforms and tools as a more engaging alternative to conventional activities. One of the engaging, and enjoyable games is Kahoot. The purpose of this study is to perceive the course content of Kahoot in the classroom to increase exam scores in vocabulary, and boost student engagement, and motivation. In addition, this study also explored the issues encountered by students in vocabulary learning through Kahoot. The impact of gamification on student achievement was assessed using quantitative and qualitative methods on the first-year students of the English department (N = 82). The findings revealed that incorporating Kahoot for teaching vocabulary effectively allows learners to expand a deeper understanding of vocabulary and course concepts indicated by exam scores improvement. This method also has a positive impact on student engagement as well as motivation. Furthermore, rigorous future research is needed to fully understand Kahoot’s efficacy and to improve pedagogy in the vocabulary classroom.
RETRACTED: The perceived service quality in higher education: An empirical study using the SERVPERF dimensions
Authors: Fuchs Kevin , Fangpong Keerati , Southam Ashleigh
Published: September 2022

Students have become more concerned about their university selection and are more demanding of the universities they chose. In this highly competitive environment, universities need to understand these expectations. This study examines how undergraduate students perceived the service quality in their higher education institution. To answer that question, a questionnaire was developed and was distributed amongst tourism and hospitality students in Thailand. A variety of statistical techniques was used to analyze the 208 eligible responses. The results revealed that year of study is a significant factor on students reported levels of service quality, whereas gender and nationality were not. This study emphasizes the need to consider the student’s year of study (e.g., age) when policymakers and educators evaluate students’ needs in undergraduate tourism education. The article concludes by presenting implications for educators, policymakers, and education researchers.
Using an extended technology acceptance model to determine students’ behavioral intentions toward smartphone technology in the classroom
Authors: Fuchs Kevin
Published: September 2022

The modern classroom takes on numerous forms and expands beyond the traditional brick-and-mortar walls. Educators are increasingly expected to integrate information and communications technology (ICT) and e-learning into the modern classroom. Several variables may influence instructors’ decision-making processes about ICT integration in the classroom. Smartphone technology provides students with accessibility, the ability to communicate with others, as well as to engage with classroom material. The study aims to examine how a variety of factors (perceived usefulness, perceived ease of use, subjective norm, and attitude) influence behavioral intention toward the use of smartphone technology. Two hundred and ninety survey responses were analyzed to identify the relationship between these factors based on an extended technology acceptance model. The empirical results of the study revealed that subjective norms and attitudes are significant predictors of behavioral intention toward the use of smartphone technology. The article concludes by presenting implications for educators, policymakers, and education researchers derived from the academic and practical discussions based on the findings.
Preclinical findings: The pharmacological targets and molecular mechanisms of ferulic acid treatment for COVID-19 and osteosarcoma via targeting autophagy
Authors: Pang Guangfu , Yi Tingzhuang , Luo Hongcheng , Jiang Lihe
Published: September 2022

The variant virus-based 2019 coronavirus disease (COVID-19) pandemic has reportedly impacted almost all populations globally, characterized by a huge number of infected individuals. Clinical evidence proves that patients with cancer are more easily infected with severe acute respiratory disease coronavirus 2 (SARS-CoV-2) because of immunologic deficiency. Thus, there is an urgent need to develop candidate medications to treat patients with cancer plus COVID-19, including those with osteosarcoma (OS). Ferulic acid, a latent theriacal compound that has anti-tumor and antivirus activities, is discovered to have potential pharmacological use. Thus, in this study, we aimed to screen and determine the potential therapeutic targets of ferulic acid in treating patients with OS plus COVID-19 as well as the pharmacological mechanisms. We applied a well-established integrated methodology, including network pharmacology and molecular docking technique, to detail target prediction, network construction, gene ontology, and pathway enrichment in core targets. The network pharmacology results show that all candidate genes, by targeting autophagy, were the core targets of ferulic acid in treating OS and COVID-19. Through molecular docking analysis, the signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase 1 (MAPK1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) were identified as the pharmacological targets of ferulic acid in treating OS. These preclinical findings from bioinformatics analysis altogether effectively determined the pharmacological molecules and mechanisms via targeting autophagy, demonstrating the therapeutic effectiveness of ferulic acid against COVID-19 and OS.
Chinese famine exposure in early life and metabolic obesity phenotype in middle age: Results from the China health and retirement longitudinal study
Authors: Xu Yunhan , Yi Qian , Shan Shiyi , Zhou Jiali , Li Shuting , Hou Leying , Ye Xinxin , Ying Jiayao , Song Peige , An Lin
Published: September 2022

Objective

To assess the association between early life exposure to famine and the risk of metabolic obesity phenotypes among adults in middle age.

Methods

The study selected two comparison groups. Comparison A consisted of a non-exposed group born between 1963-1965 from the China Health and Retirement Longitudinal Study (CHARLS) 2015 wave (N=862) and a fetal-exposed group born between 1959-1961 from the 2011 wave (N=507). Comparison B consisted of an early childhood-exposed group born between 1955-1957 from the 2011 wave (N=830) and a fetal-exposed group born between 1959-1961 from the 2015 wave (N=552). Multivariable logistic regressions were conducted to explore the associations between different periods of famine exposure and obesity, metabolic health status, and metabolic obesity phenotypes, with stratification by sex.

Results

Compared with the non-exposed group, participants exposed to famine in the fetal period had a significantly lower risk of overweight/obesity (OR: 0.78, 95%CI: 0.63-0.97) and a higher risk of metabolically unhealthy status (OR: 1.73, 95%CI: 1.34-2.23) and metabolically unhealthy non-obesity (MUNO) (OR: 2.12, 95%CI: 1.46-3.08) at the age of 50-52 years. In the sex-stratified analysis, males exposed to famine in the fetal period had a significantly lower risk of overweight/obesity (OR: 0.59, 95%CI: 0.43-0.80) and metabolically healthy obesity (MHO) (OR: 0.56, 95%CI: 0.37-0.85), while such associations were not found in females. Compared with the early childhood exposure group, participants in the fetal exposure group had a significantly lower risk of metabolic unhealthy status (OR: 0.65, 95%CI: 0.51-0.85) and MUNO (OR: 0.50, 95%CI: 0.35-0.72). Those associations were observed in both males and females.

Conclusion

Exposure to famine in early life increased the risk of metabolically unhealthy status in adulthood. Different metabolic subtypes should be identified at an early stage and followed by classification, intervention, and treatment.
Process study and CO2 emission reduction analysis of coal liquefaction residue fluidized bed pyrolysis
Authors: Tian Bo , Gao Junhu , Guo Qiang , Zhu Xiaoming , Zhang Hao , Zhu Wei , Hao Xu , Yang Chaohe , Yang Yong , Li Yong-Wang
Published: September 2022

The direct coal liquefaction process usually produces a liquefaction residue of about 30% of its coal feed. The effective utilization of the coal liquefaction residue (CLR), which contains about 80% organic matter, is of great significance for improving the oil yield of the direct liquefaction process and reducing the amount of pollution emitted from this oil-containing organic solid waste. In this study, the CLR fluidized bed pyrolysis process was studied through a fluidized bed reactor pyrolysis experiment and steady-state thermal analysis. The characteristics of CLR were first analyzed, and then the pyrolysis experiment was conducted in a fluidized bed reactor system. The experiment results show that the oil yield is 34.81% at 540°C for an ash-free feedstock using a fluidized bed pyrolysis reactor. Based on the pyrolysis experimental data and the Aspen Plus software platform, the fluidized bed pyrolysis reactor, fractionation column, coke burner, gasifier, and other equipment were modeled to compare four different process schemes. CLR pyrolysis is an endothermic reaction, and its heat is usually supplied by coke combustion, which produces significant CO2 emissions. Case studies of the pyrolysis process were performed in detail in order to reduce CO2 emissions. Thermal efficiency, carbon efficiency, solid waste discharge, and CO2 emissions of the different schemes were compared, and a flexible fluidized pyrolysis (FFP) process coupled with water electrolysis was proposed. The introduction of green hydrogen and green oxygen to the process can realize near-complete utilization of carbon and hydrogen elements in the CLR and produce high-quality liquid fuels and syngas (for further chemical synthesis), and this new process can achieve almost near-zero CO2 emission in the entire unit. This process principle can also be applied to the CO2 emission reduction of organic solid waste pyrolysis, catalytic fluid cracking, fluid coking, and so on.
Implementation of sustainable public procurement in China: An assessment using quantitative text analysis in large-scale tender documents
Authors: Cao Fuguo , Li Runyu , Cao Xiaoyan
Published: September 2022

In recent years, increasing attention has been paid worldwide to the sustainable development of the economy and society. Because of its size and prevalence, public procurement has always been a powerful policy tool used to tackle issues related to the sustainability of society, economy, and environment. China has attached high priority to sustainable development, and many aspects of sustainable public procurement (SPP) have been implemented though no official documents have referred to the concept of SPP. Therefore, little is known about the actual implementation and patterns of SPP in practice. The purpose of the study is to assess the actual implementation and patterns of SPP in China. We obtained 42,369 public procurement documents for 2015–2020 using the web crawler technique and the actual implementation of SPP was assessed through the text-mining technique. The research shows that SPP is implemented in more than 82% of the documents and appears in an upward trend in the past 6 years. Several patterns of SPP implementation are also identified. First, most documents implement more than one category of SPP. Second, small and medium-sized enterprise-oriented procurement is the most implemented SPP main category, overtaking environmentally friendly procurement only by a small margin, and the procurement for the circular economy is the least implemented. Third, there seem to be some relationships between the level of SPP implementation and the award method, tender price, and contract type. Finally, there is a substantial transformation of China’s SPP toward social aspects of SPP in recent years. Policy implications, limitations, and issues for future studies are also discussed.
Exploring the role of china’s civilized cities in attracting foreign direct investment. A way forward to sustainable socioeconomic development
Authors: Han Jiabin , Chen Ziyi , Rehman Alam , Zeeshan Muhammad
Published: September 2022

The cities dynamics and structures can be vital to attract foreign direct investment. Therefore, foreign investors prefer cities where they are confronted to lower volume or none of unexpected happening. The civilized locality is likely to be supportive in the operations of any business activity rendered by local or foreign firms. As the “highest honor” in the selection of cities, civilized cities have an important impact on attracting foreign direct investment. The paper attempts to evaluate the civilized cities as a quasi-natural experiment, and uses the staggered difference-in-difference model to evaluate the effect and mechanism of civilized cities evaluation on the FDI of selected cities. The results show that the honorary title of civilized city has a reputation of cumulative effect, and can significantly increase the scale of foreign direct investment in the city independent of the brands of low-carbon city, smart city, innovative city and pilot free trade zones. The three main ways to attract foreign investments can be materialized through enhancing urban infrastructure, attracting labor inflow and improving science and technology innovation.
The impact of environmental regulation or bargaining power on green total factor productivity: Evidence from Taiwan-funded enterprises in Chinese mainland
Authors: Huang Yanping , Li Xiapei , Liu Yu
Published: September 2022

Energy conservation and emission reduction of the manufacturing industry are of great significance for promoting China’s high-quality economic development. In this paper, the Luenberger productivity index based on the data envelopment analysis (DEA) method is used to measure the green total factor productivity (GTFP). The regression results show that, on one hand, environmental regulation on Taiwan-funded enterprises has a negative impact on the GTFP, which implies that these enterprises need to pay “compliance costs” due to the implementation of environmental regulation policies of Chinese local governments. On the other hand, Taiwan-funded enterprises who can create a large number of jobs have strong bargaining power with the local governments, hence have more opportunities to be exempted from environmental regulations to a certain extent. Therefore, in order to prevent local governments from failing to strictly implementing environmental regulations on Taiwan-funded enterprises, it is suggested that environmental protection achievements be included in the performance appraisal system for the local governments. Chinese local governments should start with a weaker enforcement of environmental regulation, by giving Taiwan-funded enterprises a certain buffer period to gradually adjust the policies intensity. Production characteristics and pollution density of Taiwan-funded enterprises should be considered when enforcing environmental regulation. It is also suggested that environmental, social and governance (ESG) scores of Taiwan-funded enterprises should be taken as a part of their credit qualifications, so as to enhance the internal motivation of energy conservation and emission reduction of these enterprises. In this way, environmental regulation will play a full role in promoting the GTFP of Taiwan-funded enterprises, and help the high-quality development of Chinese economy.
Break point identification and spatiotemporal dynamic evolution of air pollutants: An empirical study from Anhui province, east China
Authors: Wang Huajie , Gui Herong , Wang Houfeng , Liu Guijian
Published: September 2022

The new modality of inter-regional joint prevention and control is increasingly important to the integrated process of collaborative governance of air pollutants. Therefore, it has become necessary to analyze the degree of interaction among air pollutants within and between cities, master the dynamics of their spatiotemporal distribution and its influencing factors, and diagnose the primary obstacle factors. Long-term data on the concentrations of six air pollutants among 16 cities of Anhui province from 2015 to 2020 were analyzed using harmonic regression, the coupling coordination degree model, the obstacle degree model, the logarithmic mean Divisia index (LMDI), and exploratory spatial data analysis (ESDA). Over all, the annual mean concentrations of five of these pollutants (NO2, SO2, CO, PM10, and PM2.5) decreased to a certain extent over time, whereas O3 concentrations increased. The biggest decrease was observed in BZ city, where SO2 decreased by 80.60% (halving time: −2.03 ± 0.02 years), and the biggest increase was observed in CZ city, where O3 increased by 113.85% (doubling time: 1.74 ± 0.01 years). The O3 concentrations in most cities reached their break points starting in 2018, but the break points of other air pollutants appeared earlier than that of O3, mostly before 2018. With the exception of NO2 and O3, the halving times of other air pollutants were basically shorter than the doubling times. The high degree of interaction among air pollutants within and between cities contrasted sharply with the low degree of coordination. An analysis of hotspot evolution revealed that particulate matter (PM10 and PM2.5) migrated to northern Anhui, NO2 and O3 agglomerated to central Anhui, and CO eventually gathered in the Wanjiang City Belt. The primary obstacle factors of air pollutants in Anhui were particulate matter, SO2 and NO2. The seasonal differences in primary obstacle factors were most evident in 2020: NO2 dominated in winter (in 10 cities), SO2 dominated in southern Anhui, and particulate matter dominated in northern and central Anhui in spring. Other seasons were almost entirely dominated by particulate matter. Industrial structure was found to be more effective in reducing industrial carbon emissions, and technological improvement was found to be more advantageous in reducing industrial particulate matter, NOx and SO2. Finally, the policy implications of these results and suggestions for strengthening the inter-city joint prevention and control of air pollutants are discussed.
Rhizobium inoculation and exogenous melatonin synergistically increased thermotolerance by improving antioxidant defense, photosynthetic efficiency, and nitro-oxidative homeostasis in Medicago truncatula
Authors: Irshad Annie , Rehman Rana Naveed Ur , Dubey Shikha , Khan Muhammad Azam , Yang Peizhi , Hu Tianming
Published: September 2022

Global warming negatively affects plant growth due to the detrimental effects of high temperature-induced heat stress. Rhizobium inoculation (RI) and exogenous melatonin (MT) have shown a positive role in resisting abiotic stress. However, their synergistic effect on avoiding heat-induced damages in Medicago truncatula has not been studied yet. Hence, the objective of the present study was to evaluate the impact of these amendments (RI and MT) to ameliorate the heat damages in Medicago truncatula. The study was comprised of two factors: (1) heat-induced stress: (i) optimum temperature (26 ± 1°C): (23 ± 1°C) (day: night), (ii) moderate heat (35 ± 1°C): (28 ± 1°C), and (iii) severe heat (41 ± 1°C): (35 ± 1°C) for 72 h, and (2) amendments: (i) no RI + no MT (NRI + NMT), (ii) Rhizobium inoculation (RI), (iii) 60 μM melatonin (MT), and (iii) RI + MT. Results showed that the combined application of RI and MT was better than their individual applications, as it prevented heat-induced membrane damages by declining the hydrogen peroxide (34.22% and 29.78%), superoxide anion radical (29.49% and 26.71%), malondialdehyde contents (26.43% and 21.96%), and lipoxygenase activity (44.75% and 25.51%) at both heat stress levels as compared to NRI + NMT. Moreover, RI + MT treated plants showed higher antioxidative and methylglyoxal detoxification enzymes (Gly I and Gly II) activities under heat stress. While, NRI + NMT treated plants showed a higher level of methylglyoxal contents (47.99% and 46.71%) under both levels of heat stress. Relative to NRI + NMT plants, RI + MT pretreated plants exhibited improved heat tolerance as indicated by higher chlorophyll (37.42% and 43.52%), carotenoid contents (32.41% and 47.08%), and photosynthetic rate (42.62% and 64.63%), under moderate and severe heat stress, respectively. Furthermore, RI + MT pretreated plants had considerably higher indole-3 acetic acid and abscisic acid concentrations under moderate (54.02% and 53.92%) and severe (68.36% and 64.61%) heat stress conditions. Similarly, plant dry biomass, NPK uptake, nitric oxide, and nitrate reductase activity were high in RI + MT treated plants, under both levels of stress. Therefore, this study advocates the positive synergistic effect of RI and MT pretreatment against moderate and severe heat-induced stress and for possible maintenance of plant growth under changing scenarios of global warming.
Ensemble modeling to predict the impact of future climate change on the global distribution of Olea europaea subsp. cuspidata
Authors: Khan Sajid , Verma Susheel
Published: September 2022

Climate change is one of the significant factors influencing global species redistribution. As a result, a better understanding of the species' possible range change in future climate conditions is needed. Therefore, this study compiles global geographic occurrence data of a wild olive sub-species, Olea europaea subsp. cuspidate, and projected potential distribution models in current and future climate scenarios. This study using ensemble modeling predicted that the species will undergo a significant decrease in habitat suitability under future climatic conditions with a contraction ranging from ca. 41 and 42% under RCP4.5 2050 and to about 56 and 61% under RCP8.5 2070 for committee averaging and weighted mean, respectively. More specifically, there will be a decrease in habitat suitability in regions of the southeastern part of the United States in North America; coastal regions in South America; coastal regions in the majority of eastern Africa; coastal parts of Spain, France, Italy, and Greece in Europe; coastal parts of Yemen and Saudi Arabia; the southeastern parts of Pakistan and the southern part of China in Asia; and southwestern and eastern parts of Australia when compared to current habitat suitability. The results of this ensemble modeling could be extremely valuable in identifying cultivation hotspots for the effective restoration and protection of this olive lineage under future climatic conditions.
Single-cell RNA-seq analyses show that long non-coding RNAs are conspicuously expressed in Schistosoma mansoni gamete and tegument progenitor cell populations
Authors: Morales-Vicente David A. , Zhao Lu , Silveira Gilbert O. , Tahira Ana C. , Amaral Murilo S. , Collins James J. , Verjovski-Almeida Sergio
Published: September 2022

Schistosoma mansoni is a flatworm that causes schistosomiasis, a neglected tropical disease that affects over 200 million people worldwide. New therapeutic targets are needed with only one drug available for treatment and no vaccine. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with low or no protein-coding potential. In other organisms, they have been shown as involved with reproduction, stem cell maintenance and drug resistance, and they tend to exhibit tissue-specific expression patterns. S. mansoni expresses thousands of lncRNA genes; however, the cell type expression patterns of lncRNAs in the parasite remain uncharacterized. Here, we have re-analyzed publicly available single-cell RNA-sequencing (scRNA-seq) data obtained from adult S. mansoni to identify the lncRNAs signature of adult schistosome cell types. A total of 8023 lncRNAs (79% of all lncRNAs) were detected. Analyses of the lncRNAs expression profiles in the cells using statistically stringent criteria were performed to identify 74 lncRNA gene markers of cell clusters. Male gamete and tegument progenitor lineages clusters contained most of the cluster-specific lncRNA markers. We also identified lncRNA markers of specific neural clusters. Whole-mount in situ hybridization (WISH) and double fluorescence in situ hybridization were used to validate the cluster-specific expression of 13 out of 16 selected lncRNA genes (81%) in the male and female adult parasite tissues; for one of these 16 gene loci, probes for two different lncRNA isoforms were used, which showed differential isoform expression in testis and ovary. An atlas of the expression profiles across the cell clusters of all lncRNAs detected in our analysis is available as a public website resource (http://verjolab.usp.br:8081). The results presented here give strong support to a tissue-specific expression and to a regulated expression program of lncRNAs in S. mansoni. This will be the basis for further exploration of lncRNA genes as potential therapeutic targets.
The need for more holistic immune profiling in next-generation SARS-CoV-2 vaccine trials
Authors: Murphy Robert L. , Paramithiotis Eustache , Sugden Scott , Chermak Todd , Lambert Bruce , Montamat-Sicotte Damien , Mattison John , Steinhubl Steve
Published: September 2022

First-generation anit-SARS-CoV-2 vaccines were highly successful. They rapidly met an unforeseen emergency need, saved millions of lives, and simultaneously eased the burden on healthcare systems worldwide. The first-generation vaccines, however, focused too narrowly on antibody-based immunity as the sole marker of vaccine trial success, resulting in large knowledge gaps about waning vaccine protection, lack of vaccine robustness to viral mutation, and lack of efficacy in immunocompromised populations. Detailed reviews of first-generation vaccines, including their mode of action and geographical distribution, have been published elsewhere. Second-generation clinical trials must address these gaps by evaluating a broader range of immune markers, including those representing cell-mediated immunity, to ensure the most protective and long-lasting vaccines are brought to market.
Neither COVID-19, nor cryopreservation, prevented allogeneic product infusion: A report from the National Marrow Donor Program
Authors: Farhadfar Nosha , Newman Jeni , Novakovich Jennifer , Barten Jacklyn , Ndifon Eric T. , Oakes Jason , Cody Meghann , Pham Huy P. , Auletta Jeffery J. , Miller John P. , Devine Steven M. , Stefanski Heather E.
Published: September 2022

Background

The Coronavirus Disease 2019 (COVID-19) pandemic in early 2020 has resulted in an unprecedented level of uncertainty and challenge for the stem cell donor registries. To address these challenges, rapid strategies were implemented by the National Marrow Donor Registry (NMDP) and its network partners. Herein, we aim to report the impact of the COVID-19 pandemic on the collection, utilization of grafts, and short-term outcomes of patients who received stem cell products from COVID-19-positive donors.

Methods

NMDP data during the early phase (1 March 2020 through 1 May 2020) of the pandemic were compared to the later phase (1 March 2021 through 1 May 2021). Odds ratios were calculated to determine the impact of the pandemic on graft sources requested by transplant centers (TCs). The Kruskal–Wallis test was used to test the effect of the pandemic on the disease indication, volume of searches, and number of products not infused.

Results

Although there was an initial decline in overall donor searches during the early phase of the pandemic, these numbers increased reaching pre-pandemic levels during the later phase. Urgent malignant diseases remained the most common indication for transplant in 2021. The pandemic necessitated cryopreservation of stem cell products due to transportation restrictions as well as clinical uncertainties in managing the virus. Cryopreserved grafts remained the most common requested grafts throughout the pandemic. In the later phase of the pandemic, the total numbers of requests for fresh grafts increased, mostly due to the increase in requests for fresh bone marrow (BM) grafts. As the pandemic continued, TCs became more accepting of cryopreservation, resulting in a reduction in the number of products not infused. Lastly, no short-term deleterious outcomes were noted among the patients who had stem cell products infused from a SARS-CoV-2-positive donor.

Conclusion

Throughout the pandemic, the NMDP and TCs worked tirelessly to ensure that patients would receive lifesaving grafts when needed. The data reported here, although limited by small numbers, illustrate that transplantation from donors with COVID-19 is feasible and safe.
Case report: Two PD-L1 positive unresectable advanced pancreatic carcinoma patients with microsatellite stability achieved R0 resection after PD-1 antibody plus chemotherapy as a successful downstaging therapy: A report of two cases
Authors: Shang Lin , Li Peng , Fan Jie , Zhao Chunning , Niu Xiangying , Bian Qitian , Yuan Zhilin , Kong Yanlong , Zhu Tingshun , Xu Bin , Dong Jianxin , Xiang Hongjun
Published: September 2022

Background

Nonobvious early symptoms are a prominent characteristic of pancreatic cancer, resulting in only 20% of patients having resectable tumors at the time of diagnosis. The optimal management of unresectable advanced pancreatic cancer (UAPC) remains an open research question. In this study, the tumors shrank significantly after PD-1 antibody combined with chemotherapy in two UAPC patients, and both have achieved R0 (pathologically negative margin) resection and survival to date.

Case presentation

Case 1: A 53-year-old man was diagnosed with pancreatic adenocarcinoma (Stage III). He received six cycles of PD-1 antibody plus chemotherapy as the first-line treatment. The tumor was reduced from 11.8×8.8 cm to “0” (the pancreatic head was normal as shown by enhanced computed tomography, ECT) after preoperative neoadjuvant therapy (PNT) and the adverse effects were tolerable. The patient underwent radical surgery and achieved R0 resection. Case 2: A 43-year-old man diagnosed with pancreatic adenocarcinoma with liver metastasis (Stage IV) received three cycles of PD-1 antibody combined with chemotherapy. The tumor was reduced from 5.2×3.9 cm to 2.4×2.3 cm with no side effects. The patient also underwent radical surgery and achieved R0 resection.

Conclusion

PD-1 antibody plus a chemotherapy regimen resulted in a surprising curative effect and safety in two patients with UAPC, which may portend an improvement in pancreatic carcinoma treatment. We may have a way for UAPC patients to obtain radical treatment and gain long-term survival. Two PD-L1 positive UAPC patients with microsatellite stability (MSS) enlighten us to have a more comprehensive understanding of the prediction of immunotherapy.
Alterations of m6A RNA methylation regulators contribute to autophagy and immune infiltration in primary Sjögren’s syndrome
Authors: Cheng Linlin , Li Haolong , Zhan Haoting , Liu Yongmei , Li Xiaomeng , Huang Yuan , Wang Li , Zhang Fengchun , Li Yongzhe
Published: September 2022

N6-methyladenosine (m6A) RNA modification is a new epigenetic regulation mechanism on eukaryotic mRNA. Few autoimmune diseases focused on the role of m6A in their pathogenies, and m6A modulation in the pathological process of primary Sjögren’s syndrome (pSS) is still unknown. In this work, three microarray datasets of pSS patients were downloaded from the GEO database: datasets #1 and #2 from the whole peripheral blood (PB) samples, dataset #3 from the labial salivary gland tissue samples, as well as a PB cohort collected from our hospital. Six differentially expressed m6A regulators were identified by comparing the PB dataset #1 of pSS and healthy controls using the Wilcox test and logistic regression analysis. Among them, four (ALKBH5, RBMX, RBM15B, and YTHDF1) were confirmed as down-regulated in PB dataset #2 and in our PB cohort by RT-PCR, and four (ALKBH5, METTL3, RBM15B, and YTHDF1) were confirmed as down-regulated in the dataset #3 of the labial gland tissue. In addition, discrepantly expressed m6A regulators accompanied by diverse immunocytes, including dendritic cells (DCs), T cells, and CD56dim natural killer cells, and among the regulators, ALKBH5 and METTL3 were comprehensively linked with the infiltrated immune cells. Notably, the most enriched autophagy mechanism mediated by m6A was observed in pSS using functional annotation analysis. Ten hub genes were identified using a protein-protein interaction network, and their expression in PB dataset #2 and the expression of three genes (PIK3CA, STAT1, and MAPK3) in the labial gland tissue dataset #3 were confirmed. Our study provides evidence that m6A methylation is widely involved in the immune infiltration and autophagy of pSS, thus contributing to the pathogenesis of this disease and potentially representing a novel therapeutic target.
Safety and immunogenicity of 3 doses of BNT162b2 and CoronaVac in children and adults with inborn errors of immunity
Authors: Leung Daniel , Mu Xiaofeng , Duque Jaime S. Rosa , Cheng Samuel M. S. , Wang Manni , Zhang Wenyue , Zhang Yanmei , Tam Issan Y. S. , Lee Toby S. S. , Lam Jennifer H. Y. , Chan Sau Man , Cheang Cheuk Hei , Chung Yuet , Wong Howard H. W. , Lee Amos M. T. , Li Wing Yan , Chaothai Sara , Tsang Leo C. H. , Chua Gilbert T. , Cheong Kai-Ning , Au Elaine Y. L. , Kwok Janette S. Y. , Chan Koon Wing , Chong Patrick C. Y. , Lee Pamela P. W. , Ho Marco H. K. , Lee Tsz Leung , Tu Wenwei , Peiris Malik , Lau Yu Lung
Published: September 2022

Our study (NCT04800133) aimed to determine the safety and immunogenicity in patients with IEIs receiving a 3-dose primary series of mRNA vaccine BNT162b2 (age 12+) or inactivated whole-virion vaccine CoronaVac (age 3+) in Hong Kong, including Omicron BA.1 neutralization, in a nonrandomized manner. Intradermal vaccination was also studied. Thirty-nine patients were vaccinated, including 16 with homologous intramuscular 0.3ml BNT162b2 and 17 with homologous intramuscular 0.5ml CoronaVac. Two patients received 3 doses of intradermal 0.5ml CoronaVac, and 4 patients received 2 doses of intramuscular BNT162b2 and the third dose with intradermal BNT162b2. No safety concerns were identified. Inadequate S-RBD IgG and surrogate virus neutralization responses were found after 2 doses in patients with humoral immunodeficiencies and especially so against BA.1. Dose 3 of either vaccine increased S-RBD IgG response. T cell responses against SARS-CoV-2 antigens were detected in vaccinated IEI patients by intracellular cytokine staining on flow cytometry. Intradermal third dose vaccine led to high antibody response in 4 patients. The primary vaccination series of BNT162b2 and CoronaVac in adults and children with IEIs should include 3 doses for optimal immunogenicity.
Defining the role of neutrophils in the lung during infection: Implications for tuberculosis disease
Authors: Gaffney E. , Murphy D. , Walsh A. , Connolly S. , Basdeo S. A. , Keane J. , Phelan J. J.
Published: September 2022

Neutrophils are implicated in the pathogenesis of many diseases involving inflammation. Neutrophils are also critical to host defence and have a key role in the innate immune response to infection. Despite their efficiencies against a wide range of pathogens however, their ability to contain and combatMycobacterium tuberculosis(Mtb) in the lung remains uncertain and contentious. The host response to Mtb infection is very complex, involving the secretion of various cytokines and chemokines from a wide variety of immune cells, including neutrophils, macrophages, monocytes, T cells, B cells, NK cells and dendritic cells. Considering the contributing role neutrophils play in the advancement of many diseases, understanding how an inflammatory microenvironment affects neutrophils, and how neutrophils interact with other immune cells, particularly in the context of the infected lung, may aid the design of immunomodulatory therapies. In the current review, we provide a brief overview of the mechanisms that underpin pathogen clearance by neutrophils and discuss their role in the context of Mtb and non-Mtb infection. Next, we examine the current evidence demonstrating how neutrophils interact with a range of human and non-human immune cells and how these interactions can differentially prime, activate and alter a repertoire of neutrophil effector functions. Furthermore, we discuss the metabolic pathways employed by neutrophils in modulating their response to activation, pathogen stimulation and infection. To conclude, we highlight knowledge gaps in the field and discuss plausible novel drug treatments that target host neutrophil metabolism and function which could hold therapeutic potential for people suffering from respiratory infections.
Circulating CD81-expressing extracellular vesicles as biomarkers of response for immune-checkpoint inhibitors in advanced NSCLC
Authors: Signorelli Diego , Ghidotti Patrizia , Proto Claudia , Brambilla Marta , De Toma Alessandro , Ferrara Roberto , Galli Giulia , Ganzinelli Monica , Lo Russo Giuseppe , Prelaj Arsela , Occhipinti Mario , Viscardi Giuseppe , Capizzuto Valentina , Pontis Francesca , Petraroia Ilaria , Ferretti Anna Maria , Colombo Mario Paolo , Torri Valter , Sozzi Gabriella , Garassino Marina Chiara , Jachetti Elena , Fortunato Orazio
Published: September 2022

PD-L1 in tumor cells is the only used biomarker for anti PD1/PD-L1 immune-checkpoints inhibitors (ICI) in Non Small Cell Lung Cancer (NSCLC) patients. However, this parameter is inaccurate to predict response, especially in patients with low tumor PD-L1. Here, we evaluated circulating EVs as possible biomarkers for ICI in advanced NSCLC patients with low tumoral PD-L1. EVs were isolated from plasma of 64 PD-L1 low, ICI-treated NSCLC patients, classified either as responders (R; complete or partial response by RECIST 1.1) or non-responders (NR). EVs were characterized following MISEV guidelines and by flow cytometry. T cells from healthy donors were triggered in vitro using patients’ EVs. Unsupervised statistical approach was applied to correlate EVs’ and patients’ features to clinical response. R-EVs showed higher levels of tetraspanins (CD9, CD81, CD63) than NR-EVs, significantly associated to better overall response rate (ORR). In multivariable analysis CD81-EVs correlated with ORR. Unsupervised analysis revealed a cluster of variables on EVs, including tetraspanins, significantly associated with ORR and improved survival. R-EVs expressed more costimulatory molecules than NR-EVs although both increased T cell proliferation and partially, activation. Tetraspanins levels on EVs could represent promising biomarkers for ICI response in NSCLC.
Blood gene expression predicts intensive care unit admission in hospitalised patients with COVID-19
Authors: Penrice-Randal Rebekah , Dong Xiaofeng , Shapanis Andrew George , Gardner Aaron , Harding Nicholas , Legebeke Jelmer , Lord Jenny , Vallejo Andres F. , Poole Stephen , Brendish Nathan J. , Hartley Catherine , Williams Anthony P. , Wheway Gabrielle , Polak Marta E. , Strazzeri Fabio , Schofield James P. R. , Skipp Paul J. , Hiscox Julian A. , Clark Tristan W. , Baralle Diana
Published: September 2022

Background

The COVID-19 pandemic has created pressure on healthcare systems worldwide. Tools that can stratify individuals according to prognosis could allow for more efficient allocation of healthcare resources and thus improved patient outcomes. It is currently unclear if blood gene expression signatures derived from patients at the point of admission to hospital could provide useful prognostic information.

Methods

Gene expression of whole blood obtained at the point of admission from a cohort of 78 patients hospitalised with COVID-19 during the first wave was measured by high resolution RNA sequencing. Gene signatures predictive of admission to Intensive Care Unit were identified and tested using machine learning and topological data analysis, TopMD.

Results

The best gene expression signature predictive of ICU admission was defined using topological data analysis with an accuracy: 0.72 and ROC AUC: 0.76. The gene signature was primarily based on differentially activated pathways controlling epidermal growth factor receptor (EGFR) presentation, Peroxisome proliferator-activated receptor alpha (PPAR-α) signalling and Transforming growth factor beta (TGF-β) signalling.

Conclusions

Gene expression signatures from blood taken at the point of admission to hospital predicted ICU admission of treatment naïve patients with COVID-19.
The impact of CoronaVac on the neutralization breadth and magnitude of the antibody response to SARS-CoV-2 viruses
Authors: Zhang Lu , Chen Hongquan , Yang Su , Zhao Yang , Shen Xiaoyun , He Xiaowen , Ye Haohui , Wang Deqin , Lou Jiazhou , Wang Yinshan , Wu Shengjun
Published: September 2022

Although immune response enhancement has been reported after primary and booster vaccines of CoronaVac, neutralization breadth of SARS-CoV-2 variants is still unclear. In the present study, we examined the neutralization magnitude and breadth of SARS-CoV-2 variants including Beta (B.1.351), Delta (B.1.617.2) and Omicron (B.1.1.529) in 33 convalescent COVID-19 patients and a cohort of 55 medical staff receiving primary CoronaVac vaccines and an additional homologous booster dose. Results showed that, as compared with the two-dose primary vaccination, the homologous booster dose achieved 2.24-, 3.98-, 4.58- and 2.90-fold increase in neutralization titer against wild-type, Beta, Delta, and Omicron, respectively. After booster dose, neutralization titer reduction for variants was less than that after the primary vaccine or that for convalescents. The proportion of recipients able to neutralize 2 or more variants increased from 36.36% post the primary vaccination to 87.27% after the booster. Significant increase in neutralization breadth of 1.24 (95% confidence interval (CI), 0.89–1.59) variants was associated with a log10 increase in neutralization titer against the wild-type. In addition, anti-RBD IgG level was identified as an excellent surrogate for positive neutralization of SARS-CoV-2 and neutralization breadth of variants. These findings highlight the value of an additional homologous CoronaVac dose in broadening the cross-neutralization against SARS-CoV-2 variants, and are critical for informing the booster dose vaccination efforts.
HBV immune tolerance of HBs-transgenic mice observed through parabiosis with WT mice
Authors: Zhang Wendi , Sun Haoyu , Sun Rui , Lian Zhexiong , Wei Haiming , Tian Zhigang , Chen Yongyan
Published: September 2022

It was extensively recognized that central tolerance to HBV exists in HBs-transgenic (Tg) mice, however, the immune response to HBV vaccine may be inspired in adult HBs-Tg mice after boosting with potent adjuvants, leaving a mystery to explore its immune tolerance. Here, WT-HBs-Tg parabiotic mice model was generated by conjoining WT (donor) and HBs-Tg (host) mouseviaparabiotic surgery, in order to see how immunocompetent WT mice naturally respond to HBV, and how tolerant HBs-Tg mice influence the anti-HBV immunity from WT mice. It was found that WT CD8+T cells markedly accumulated into the liver of HBs-Tg parabionts, and importantly, almost all HBsAg-specific CD8+T cells derived from WT but not HBs-Tg mice, making a clear separation of a normal immune response from WT donor and a tolerant response by recipient host. Further, in the absence of host but not donor spleen, HBsAg-specific CD8+T cells disappeared, indicating that host spleen was the indispensable site for donor HBsAg-specific CD8+T cell priming though its mechanisms need further study. We found that donor CD4+T helper cells were necessary for donor HBsAg-specific CD8+T cell response by CD4-deficiency in WT or in HBs-Tg mice, indicating that an immune response was elicited between CD4+T helper cells and CD8+cytotoxic T cells of donor in the host but not donor spleen. It was noted that compared to donor CD4+T cells, host CD4+T cells were characterized with more tolerant features by harboring more CD25+Foxp3+Tregs with higher expression of PD-1 and TIGIT in the spleen of HBs-Tg parabionts, which exhibited suppressive function on CD8+T cells directly. Moreover, the Th1/Treg ratio was enhanced after parabiosis, suggesting that donor T helper cells may overcome the negative regulation of host Tregs in host spleen. In conclusion, both incompetent anti-HBV CD8+T cells and insufficient help from CD4+T cells are the major mechanisms underlying immune tolerance in HBs-Tg mice which helps explain HBV persistence.
Epitranscriptome profiling of spleen mRNA m6A methylation reveals pathways of host responses to malaria parasite infection
Authors: Wang Luoluo , Wu Jian , Liu Runzhou , Chen Wenjun , Pang Zhichang , Zhou Fan , Xia Lu , Huang Jia , Pan Tao , Su Xin-zhuan , Wang Xiaoyun
Published: September 2022

N6-Methyladenosine (m6A), the most abundant mammalian mRNA modification, has been reported to modulate various viral infections. Although it has been confirmed that RNA modifications can also modulate the replication and development of different parasites, the role of the RNA epitranscriptome in the regulation of host response post parasite infection remains to be elucidated. Here we report host spleen m6A epitranscriptome landscapes induced by different strains of the malaria parasite Plasmodium yoelii. We found that malaria parasite infection dramatically changes host spleen m6A mRNA modification and gene expression. Additionally, malaria parasite infection reprograms host immune response pathways by regulating the m6A modification enzymes. Collectively, our study is the first characterization of host spleen m6A methylome triggered by malaria parasite infections, and our data identify m6A modifications as significant transcriptome-wide marks during host-parasite interactions. We demonstrate that host mRNA methylation machinery can sense and respond to malaria parasite infections, and provide new insights into epitranscriptomic mechanisms underlying parasite-induced pathogenesis.