bluuebunny/crossref_metadata_2025 huggingface dataset:
An NFIX-mediated regulatory network governs the balance of hematopoietic stem and progenitor cells during hematopoiesis
Authors: Walker Megan , Li Yichao , Morales-Hernandez Antonio , Qi Qian , Parupalli Chaithanyarani , Brown Scott , Christian Claiborne , Clements Wilson K. , Cheng Yong , McKinney-Freeman Shannon
Published: December 2022

The transcription factor (TF) nuclear factor I-X (NFIX) is a positive regulator of hematopoietic stem and progenitor cell (HSPC) transplantation. Nfix-deficient HSPCs exhibit a severe loss of repopulating activity, increased apoptosis, and a loss of colony-forming potential. However, the underlying mechanism remains elusive. Here, we performed cellular indexing of transcriptomes and epitopes by high-throughput sequencing (CITE-seq) on Nfix-deficient HSPCs and observed a loss of long-term hematopoietic stem cells and an accumulation of megakaryocyte and myelo-erythroid progenitors. The genome-wide binding profile of NFIX in primitive murine hematopoietic cells revealed its colocalization with other hematopoietic TFs, such as PU.1. We confirmed the physical interaction between NFIX and PU.1 and demonstrated that the 2 TFs co-occupy super-enhancers and regulate genes implicated in cellular respiration and hematopoietic differentiation. In addition, we provide evidence suggesting that the absence of NFIX negatively affects PU.1 binding at some genomic loci. Our data support a model in which NFIX collaborates with PU.1 at super-enhancers to promote the differentiation and homeostatic balance of hematopoietic progenitors.
Thrombin-mediated activation of PAR1 enhances doxorubicin-induced cardiac injury in mice
Authors: Grover Steven P. , Bharathi Vanthana , Posma Jens J. , Griffin John H. , Palumbo Joseph S. , Mackman Nigel , Antoniak Silvio
Published: December 2022

The chemotherapeutic drug doxorubicin is cardiotoxic and can cause irreversible heart failure. In addition to being cardiotoxic, doxorubicin also induces the activation of coagulation. We determined the effect of thrombin-mediated activation of protease-activated receptor 1 (PAR1) on doxorubicin-induced cardiac injury. Administration of doxorubicin to mice resulted in a significant increase in plasma prothrombin fragment 1+2, thrombin-antithrombin complexes, and extracellular vesicle tissue factor activity. Doxorubicin-treated mice expressing low levels of tissue factor, but not factor XII-deficient mice, had reduced plasma thrombin-antithrombin complexes compared to controls. To evaluate the role of thrombin-mediated activation of PAR1, transgenic mice insensitive to thrombin (Par1R41Q) or activated protein C (Par1R46Q) were subjected to acute and chronic models of doxorubicin-induced cardiac injury and compared with Par1 wild-type (Par1+/+) and PAR1 deficient (Par1-/-) mice. Par1R41Q and Par1-/- mice, but not Par1R46Q mice, demonstrated similar reductions in the cardiac injury marker cardiac troponin I, preserved cardiac function, and reduced cardiac fibrosis compared to Par1+/+ controls after administration of doxorubicin. Furthermore, inhibition of Gαq signaling downstream of PAR1 with the small molecule inhibitor Q94 significantly preserved cardiac function in Par1+/+ mice, but not in Par1R41Q mice subjected to the acute model of cardiac injury when compared to vehicle controls. In addition, mice with PAR1 deleted in either cardiomyocytes or cardiac fibroblasts demonstrated reduced cardiac injury compared to controls. Taken together, these data suggest that thrombin-mediated activation of PAR1 contributes to doxorubicin-induced cardiac injury.
Targeting RARA overexpression with tamibarotene, a potent and selective RARα agonist, is a novel approach in AML
Authors: de Botton Stéphane , Cluzeau Thomas , Vigil Carlos , Cook Rachel J. , Rousselot Philippe , Rizzieri David A. , Liesveld Jane L. , Fenaux Pierre , Braun Thorsten , Banos Anne , Jurcic Joseph G. , Sekeres Mikkael A. , Savona Michael R. , Roboz Gail J. , Bixby Dale , Madigan Kate , Volkert Angela , Stephens Kristin , Kang-Fortner Qing , Baker Kristen , Paul Sofia , McKeown Michael , Carulli John , Eaton Matthew , Hodgson Graeme , Fiore Christopher , Kelly Michael J. , Roth David A. , Stein Eytan M.
Published: December 2022

A superenhancer at the retinoic acid receptor alpha (RARA) gene is associated with RARA mRNA overexpression in ∼30% of non-acute promyelocytic leukemia acute myeloid leukemia (AML) and in ∼50% of myelodysplastic syndromes (MDS). RARA overexpression is an actionable target for treatment with tamibarotene, an oral potent and selective RARα agonist. Sensitivity to the RARα agonist tamibarotene was demonstrated in RARA-high but not RARA-low preclinical AML models. The combination of oral tamibarotene plus azacitidine was evaluated in a phase 2 clinical study in 51 newly diagnosed unfit patients with AML identified as RARA-positive (n = 22) or RARA-negative (n = 29) for RARA mRNA overexpression in peripheral blasts using a blood-based biomarker test. In 18 response-evaluable RARA-positive patients, complete remission (CR)/CR with incomplete hematologic recovery rate was 61%, CR rate was 50%, and time to initial composite CR was rapid at 1.2 months. Transfusion independence was attained by 72% of RARA-positive patients. In contrast, 28 response-evaluable RARA-negative patients had response rates that were consistent with azacitidine monotherapy. Tamibarotene in combination with azacitidine was well tolerated. The majority of nonhematologic adverse events were low grade and hematologic adverse events were comparable to single-agent azacitidine, demonstrating that there was no additional myelosuppression when tamibarotene was combined with azacitidine. These results support further evaluation of tamibarotene-based treatment strategies in patients with AML or MDS with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial was registered at www.clinicaltrials.gov as #NCT02807558.
Absent in melanoma 2 (AIM2) in rheumatoid arthritis: novel molecular insights and implications
Authors: Zhao Jianan , Guo Shicheng , Schrodi Steven J. , He Dongyi
Published: December 2022

Absent in melanoma 2 (AIM2), a member of the Pyrin and HIN domain protein family, is a cytoplasmic receptor that recognizes double-stranded DNA. AIM2 exhibits limited expression under physiological conditions but is widely expressed in many human diseases, including autoimmune diseases, and plays an essential role in the immune response. Rheumatoid arthritis (RA) is an autoimmune disease that poses a severe threat to physical and mental health, and is caused by several genetic and metabolic factors. Multiple immune cells interact to form a complex inflammatory network that mediates inflammatory responses and bone destruction. Abnormal AIM2 expression in multiple immune cell populations (T cells, B cells, fibroblast-like synoviocytes, monocytes, and macrophages) may regulate multiple functional responses in RA through mechanisms such as pyroptosis, PANoptosis, and regulation of other molecules. In this review, we describe and summarize the functional regulation and impact of AIM2 expression in immune cells to improve our understanding of the complex pathological mechanisms. These insights may provide potential directions for the development of new clinical diagnostic strategies for RA.
RUNX3 mediates keloid fibroblast proliferation through deacetylation of EZH2 by SIRT1
Authors: Liu Hanye , Yan Guanghai , Li Li , Wang Dandan , Wang Yu , Jin Shan , Jin Zhehu , Li Liangchang , Zhu Lianhua
Published: December 2022

Background

Keloid is a benign proliferative fibrous disease featured by excessive fibroblast proliferation after skin injury. However, the mechanism of abnormal cell proliferation is still unclear. Herein, we investigated the mechanism of abnormal proliferation in keloids involving Sirtuin 1(SIRT1)/ Zeste Homolog 2 (EZH2)/ Runt-related transcription factor 3 (RUNX3). 

Methods

HE staining was used to observe the histopathological changes. Western blot was performed to detect SIRT1/EZH2/RUNX3 and cell cycle related proteins. RT-PCR detected EZH2 mRNA. After knockdown of EZH2 or overexpression of RUNX3, cell proliferation and cell cycle was analyzed. Immunoprecipitation was used to detect acetylated EZH2.

Results

The results showed that overexpression of RUNX3 inhibited cell proliferation and arrested cell cycle at G1/S phase, whereas inhibition of SIRT1 promoted cell proliferation and G1/S phase of the cell cycle. Knockdown of EZH2 promoted the expression of RUNX3, inhibited cell proliferation and shortened the progression of G1 to S phase. Simultaneous knockdown of EZH2 and inhibition of SIRT1 reversed these effects. Inhibition of SIRT1 increased its protein stability by increasing EZH2 acetylation, thereby reducing the expression of RUNX3 and promoting cell proliferation.

Conclusions

Conclusively, the SIRT1/EZH2/RUNX3 axis may be an important pathway in the regulation of abnormal proliferation in keloids.
Genome-wide identification and gene expression analysis of the 14–3-3 gene family in potato (Solanum tuberosum L.)
Authors: He Feiyan , Duan Shaoguang , Jian Yinqiao , Xu Jianfei , Hu Jun , Zhang Zhicheng , Lin Tuanrong , Cheng Feng , Li Guangcun
Published: December 2022

Background

14–3-3 proteins are essential in regulating various biological processes and abiotic stress responses in plants. Although 14–3-3 proteins have been studied in model plants such as Arabidopsis thaliana and Oryza sativa, there is a lack of research on the 14–3-3 gene family in potatoes (Solanum tuberosum L.).

Results

A total of 18 14–3-3 genes encoding proteins containing a typical conserved PF00244 domain were identified by genome-wide analysis in potatoes. The St14–3-3 gene family members were unevenly distributed across the chromosomes, and gene structure analysis showed that gene length and intron number varied greatly among the members. Phylogenetic analysis of 14–3-3 proteins in potatoes and other plant species showed that they could be divided into two distinct groups (ε and non-ε). Members in the ε group tended to have similar exon-intron structures and conserved motif patterns. Promoter sequence analysis showed that the St14–3-3 gene promoters contained multiple hormone-, stress-, and light-responsive cis-regulatory elements. Synteny analysis suggested that segmental duplication events contributed to the expansion of the St14–3-3 gene family in potatoes. The observed syntenic relationships between some 14–3-3 genes from potato, Arabidopsis, and tomato suggest that they evolved from a common ancestor. RNA-seq data showed that St14–3-3 genes were expressed in all tissues of potatoes but that their expression patterns were different. qRT-PCR assays revealed that the expression levels of nearly all tested St14–3-3 genes were affected by drought, salt, and low-temperature stresses and that different St14–3-3 genes had different responses to these stresses.

Conclusions

In summary, genome-wide identification, evolutionary, and expression analyses of the 14–3-3 gene family in potato were conducted. These results provide important information for further studies on the function and regulation of St14–3-3 gene family members in potatoes.
A comparative analysis of mitochondrial ORFs provides new insights on expansion of mitochondrial genome size in Arcidae
Authors: Zhang Ning , Li Yuanning , Halanych Kenneth M. , Kong Lingfeng , Li Qi
Published: December 2022

Background

Arcidae, comprising about 260 species of ark shells, is an ecologically and economically important lineage of bivalve mollusks. Interestingly, mitochondrial genomes of several Arcidae species are 2–3 times larger than those of most bilaterians, and are among the largest bilaterian mitochondrial genomes reported to date. The large mitochondrial genome size is mainly due to expansion of unassigned regions (regions that are functionally unassigned). Previous work on unassigned regions of Arcidae mtDNA genomes has focused on nucleotide-level analyses to observe sequence characteristics, however the origin of expansion remains unclear.

Results

We assembled six new mitogenomes and sequenced six transcriptomes of Scapharca broughtonii to identify conserved functional ORFs that are transcribed in unassigned regions. Sixteen lineage-specific ORFs with different copy numbers were identified from seven Arcidae species, and 11 of 16 ORFs were expressed and likely biologically active. Unassigned regions of 32 Arcidae mitogenomes were compared to verify the presence of these novel mitochondrial ORFs and their distribution. Strikingly, multiple structural analyses and functional prediction suggested that these additional mtDNA-encoded proteins have potential functional significance. In addition, our results also revealed that the ORFs have a strong connection to the expansion of Arcidae mitochondrial genomes and their large-scale duplication play an important role in multiple expansion events. We discussed the possible origin of ORFs and hypothesized that these ORFs may originate from duplication of mitochondrial genes.

Conclusions

The presence of lineage-specific mitochondrial ORFs with transcriptional activity and potential functional significance supports novel features for Arcidae mitochondrial genomes. Given our observation and analyses, these ORFs may be products of mitochondrial gene duplication. These findings shed light on the origin and function of novel mitochondrial genes in bivalves and provide new insights into evolution of mitochondrial genome size in metazoans.
Characterization of regulatory T cells in SARS-CoV-2 infected hemodialysis patients: relation to clinical and radiological severity
Authors: Samaan Emad , Elmaria Marwa O , Khedr Doaa , Gaber Tamer , Elsayed Ahmed G , Shenouda Ragy N , Gamal Hend , Shahin Doaa , Abousamra Nashwa K , Shemies Rasha
Published: December 2022

Background

Disordered Treg counts and function have been observed in patients with SARS-Cov-2 and are thought to contribute to disease severity. In hemodialysis patients, scarce data are available on the Treg response to SARS-CoV-2 or its relation to the clinical presentation.

Methods

A cross-sectional study included one hundred patients divided into three groups, thirty SARS-CoV-2-infected hemodialysis patients (COV-HD), and thirty confirmed SARSCoV-2 infected patients (COV), and forty non-infected hemodialysis patients (HD). Flow cytometric analysis of CD4, CD25, FoxP3, and CD39+ Tregs was done for all patients and tested for correlation to in-hospital mortality, clinical, radiological severity indices.

Results

COV-HD and COV patients had significantly lower Treg cell count than HD patients (Median value of 0.016 cell/ μl vs 0.28 cell/ μl, respectively- P: 0.001). COV-HD patients had higher CD39+ Tregs (median value of 0.006 cell/ μl vs 0.002 cell/ μl, respectively- P: 0.04). COV-HD patients had significantly lower hospital stay (median value of 3 vs 13 days, P:0.001), ICU admission rates (26.5% vs 46.7%, P:0.005) and in-hospital mortality (20.7% versus 43.3%, P:0.003) than COV patients. Treg and CD39 expressing Treg counts were not correlated to severity indices in both groups. A high neutrophil to lymphocyte ratio is strongly correlated to disease severity in COV-HD patients.

Conclusions

This study provides evidence of T-cell, particularly T-regulatory cell decline in SARS-CoV-2 and suggests that hemodialysis per se does not distinctively impact the T-cell response. COV-HD patients exhibited a higher CD39+ Treg count and a better clinical profile, however, larger studies are needed to extrapolate on these findings.
Myasthenia gravis - a retrospective analysis of e-mail inquiries made to a patient organisation and specialized center to uncover unmet needs from patients and caregivers
Authors: Stein Maike , Hoffmann Sarah , Gerischer Lea , Stascheit Frauke , Legg David , Meisel Andreas , Lehnerer Sophie
Published: December 2022

Background and aims

Myasthenia Gravis requires expert treatment from specialized neurologists. In Germany, this treatment is mainly provided by 18 Integrated Myasthenia Centers (iMZ) accredited by the German Myasthenia Gravis Association (DMG). The DMG is a large and well-organized patient organisation that is regarded as a trusted source for disease-specific information. The aim of this study was to analyse the type of requests that each of these institutions receives in order to identify any potential unmet needs regarding the availability of advice for patients and caregivers. This data can then be used in further research to tailor modern digital communication tools to the specific needs of MG patients.

Methods

Counselling requests sent via e-mail to both institutions were extracted for defined examination periods and divided into a period ‘before COVID-19 pandemic’ (01.07.2019–31.12.2019) and ‘during COVID-19 pandemic’ (01.07.2020–31.12.2020). Requests were then analysed using four main categories: medical requests, organisational issues, COVID-19 and social legislation inquiries.

Results

One thousand seven hundred eleven requests for advice were addressed to DMG and iMZ Charité. Most inquiries directed to the DMG (47%; n = 750) were related to medical issues, most frequently to side effects of medications (n = 325; 20%) and questions about treatment (n = 263; 16%), followed by inquiries regarding organisational issues (26%; n = 412). About half of the inquiries (n = 69; 58%) to the iMZ Charité were related to medical issues and almost one in three inquiries concerned organisational issues (n = 37; 30%). About one in ten inquiries concerned socio-legal matters (iMZ: n = 7; 6% and DMG: n = 177; 11%). During the pandemic, COVID-19 related issues accounted for 8% (n = 6) of inquiries at iMZ, and 16% (n = 253) at DMG.

Conclusions

MG sufferers have a high demand for timely advice. In the current setting, they address their requests to both iMZs and the DMG via e-mail. Our findings confirm that the DMG is highly trusted by patients and caregivers and is used to obtain second opinions. A relevant proportion of requests to the iMZ could be answered more effectively through standardized responses or improved process management. The implementation of modern digital solutions, including telemedicine, for communication between patient and specialist should be evaluated in further research.
16p13.11 microdeletion/microduplication in fetuses: investigation of associated ultrasound phenotypes, genetic anomalies, and pregnancy outcome follow-up
Authors: Cai Meiying , Que Yanting , Chen Xuemei , Chen Yuqing , Liang Bin , Huang Hailong , Xu Liangpu , Lin Na
Published: December 2022

Objectives

16p13.11 microdeletion/microduplication are rare genetic diseases with incomplete penetrance, most of which have been reported in adults and children, with ultrasound phenotyping in fetuses rarely described. Here, we have analyzed prenatal ultrasound phenotypic characteristics associated with 16p13.11 microdeletion/microduplication, in order to improve the understanding, diagnosis and monitoring of this disease in the fetus.

Methods

A total of 9000 pregnant women who underwent invasive prenatal diagnosis for karyotyping and SNP-array were retrospectively analyzed in tertiary referral institutions from October 2016 to January 2022.

Results

SNP-array revealed that 20 fetuses had copy number variation (CNV) in the 16p13.11 region, out of which 5 had 16p13.11 microdeletion and the rest showed microduplication, along with different ultrasound phenotypes. Furthermore, 4/20 cases demonstrated structural abnormalities, while the remaining 16 cases were atypical in ultrasound. Taken together, 16p13.1 microdeletion was closely related to thickened nuchal translucency, while 16p13.11 microduplication was more closely associated with echogenic bowel. Only 5/15 fetuses were verified by pedigree, with one case of 16p13.11 microdeletion being de novo, and the other cases of 16p13.11 microduplication were inherited from one parent. In 4/20 cases, the pregnancy was terminated. Except for one case with short stature and another one who underwent lung cystadenoma surgery, no abnormalities were reported in the other cases during follow-up.

Conclusion

Fetuses with 16p13.11 microdeletion/microduplication had no characteristic phenotype of intrauterine ultrasound and was in good health after birth, thus providing a reference for the perinatal management of such cases.
Transcription factor c-Jun modulates GLUT1 in glycolysis and breast cancer metastasis
Authors: Zhu Ping , Liu Guoping , Wang Xue , Lu Jingjing , Zhou Yue , Chen Shuyi , Gao Yabiao , Wang Chaofu , Yu Jerry , Sun Yangbai , Zhou Ping
Published: December 2022

As the main isoforms of membranous glucose transporters (GLUT), GLUT1 involves tumorigenesis, metastasis and prognosis in a variety of cancers. However, its role in breast cancer metastasis remains to be elucidated. Here we examined its transcriptional and survival data in patients with breast cancer from several independent databases including the Oncomine, Gene Expression Profiling Interactive Analysis, Gene Expression across Normal and Tumor tissue, UALCAN, cBioPortal, Kaplan-Meier Plotter and PROGgeneV2. We found that its mRNA expression was significantly high in cancer tissues, which was associated with metastasis and poor survival. Transcription factor c-Jun might bind to GLUT1 promoter to downregulate its gene expression or mRNA stability, therefore to suppress glycolysis and metastasis. By qRT-PCR, we verified that GLUT1 was significantly increased in 38 paired human breast cancer samples while JUN was decreased. Furthermore, the protein level of GLUT1 was higher in tumor than in normal tissues by IHC assay. To explore underlying pathways, we further performed GO and KEGG analysis of genes related to GLUT1 and JUN and found that GLUT1 was increased by transcription factor c-Jun in breast cancer tissues to influence glycolysis and breast cancer metastasis.
Patterns of mortality risk among patients with substance use disorder: an opportunity for proactive patient safety?
Authors: Svensson Jakob , Bergström Johan , Kåberg Martin , Becker Per
Published: December 2022

Background

Patients with substance use disorder (SUD) suffer from excess mortality compared to the overall population. This study aims to identify patterns in death rates among patients with SUD visiting a SUD emergency ward and to explore whether this knowledge can be used as input to identify patients at risk and increase patient safety.

Methods

Hospital visit data to a SUD emergency ward were collected between 2010 and 2020 through medical records. Data included gender, age, SUD diagnosis, and the time of death. The Kruskal-Wallis rank sum test was used to test between ordinal variables, and risk ratio was used to quantify the difference in mortality risk. All statistical tests were two-sided, with a 95% confidence interval and a minimum significance level of 0.05.

Results

The male patients in the study group had 1.41–1.59 higher mortality risk than the female patients. The study revealed an average death rate of 0.14 among all patients during the study period. Although patients with a diagnosed alcohol use disorder constituted 73.7% of the cohort, having an opioid use disorder or sedative hypnotics use disorder was associated with the highest death rates; 1.29–1.52 and 1.47–1.74 higher mortality risk than those without such diagnoses.

Conclusion

This study demonstrates that data from visits to SUD emergency wards can be used to identify mortality risk factors, such as gender, type of diagnosis, number of diagnoses, and number of visits to the SUD emergency ward. Knowledge about patterns of patient visits and mortality risk could be used to increase patient safety through a decision support tool integrated with the electronic medical records. An improved system for early detection of increased mortality risk offers an opportunity for an adaptive patient safety system.
An exploration of registered dietitian accreditation system development in China
Authors: Yajie Zhang , Xiaoli Wang , Ya Liu , Xiuhua Shen , Rong Xiao , Huilian Zhu , Guo Zeng , Wei Cai , Aiguo Ma , Yuexin Yang
Published: December 2022

The registered dietitian system started late in China, and since 2014 a working committee of registered dietitians has been formed by the Chinese Nutrition Society to establish a national accreditation system in accordance with the international standard academic and internship requirements. The data from the certification examinations and registrations were collected and analyzed. 8,328 registered dietitians were included in the study, with 5,673 registered dietitians (RD) and 2,655 registered dietetic technicians (DTR). Among them, 45.27% of RDs have master degree or above, and 66.44% of DTRs have bachelor or above. 53.25% RDs work in medical institutions, 14.77% in colleges and universities, and 14.56% in enterprises; 48.21% DTRs work in the medical institutions, 30.28% in enterprises, and 7.34% in the community. Although six years of work has initially established a foundation of standardized registered dietitian accreditation system, the problems of limited resources for academic education and the lack of legislative protection for the profession remain prominent.
CRISP method with flipped classroom approach in ECG teaching of arrhythmia for trainee nurses: a randomized controlled study
Authors: Wen Heling , Hong Min , Chen Fuli , Jiang Xiaoyan , Zhang Rui , Zeng Jianhui , Peng Lei , Chen Yu
Published: December 2022

Background

This study aimed to explored the effects of the Cardiac Rhythm Identification for Simple People (CRISP) method with flipped classroom approach for arrhythmia interpretation in electrocardiogram (ECG) by trainee nurses.

Methods

A total of 120 trainee nurses were enrolled and randomly divided into the experimental group and the control group using lecture-based learning method. We observed the effects of the two methods in ECG interpretation training and investigated the students’ attitudes toward the teaching practices.

Results

After training, the ECG test scores in the experimental group were significantly higher than that of the control group. Six months later, the ECG test scores of the experimental group was still higher. Self-learning enthusiasm, understanding of teaching content, satisfaction of teaching mode, satisfaction of teaching effectiveness, and interest in learning ECG were significantly higher in the experimental group.

Conclusion

CRISP method with flipped classroom approach is a new and effective mode worth trying in ECG teaching for trainee nurses.
Genetic analysis of genome sequence characteristics of two lumpy skin disease viruses isolated from China
Authors: Li Lin , Wang Zhenzhong , Qi Chuanxiang , Liu Shan , Gong Mingxia , Li Jinming , Wu Xiaodong , Wang Zhiliang
Published: December 2022

Background

Lumpy skin disease (LSD) is an acute or subacute infectious disease caused by lumpy skin disease virus (LSDV) of genus Capripoxvirus. The outbreaks of LSD were confirmed in the Yili area of the Xinjiang autonomous region in August 2019 and the Fujian province in June 2020. We detected LSDV in our daily monitoring work, then isolated, identified and sequenced the virus, and analyzed the whole genome characteristics of the isolated strain.

Results

Whole genome sequencing revealed that the strains isolated were all LSDV and were named as LSDV XJ201901 and LSDV FJ2019. The results showed that the identity based on whole genome sequences between LSDV XJ201901 and LSDV FJ2019 was 100% and the identity based on whole genome sequences between the two isolated strains and the global LSDV strains was 97.28%-99.99%, with the strain LSDV72/PrachuapKhiriKhan/Thailand/2021 (99.99%) having the highest sequence identity. Analysis of potential recombination events revealed that a total of 18 potential recombination events were identified in strains LSDV XJ201901 and LSDV FJ2019. The two strains are a recombination of Neethling vaccine LW 1959 (GeneBank: AF409138.1) with KSGP 0240 (GeneBank: KX683219.1). It was observed that Neethling vaccine LW 1959 (11/18) and KSGP 0240 (10/18) are involved in most of the potential recombination events.

Conclusions

The virus isolate in this study was LSDV and was identified as a vaccine recombinant strain. The most likely potential parent strains of the two strains in this study are Neethling vaccine LW 1959 and KSGP 0240. The strains in this study are very similar to those isolated in East and Southeast Asia since 2019.
Efficacy of Global Leadership Initiative on Malnutrition as potential cachexia screening tool for patients with solid cancer
Authors: Song Mengmeng , Zhang Qi , Liu Tong , Tang Meng , Zhang Xi , Ruan Guotian , Zhang Xiaowei , Zhang Kangping , Ge Yizhong , Yang Ming , Li Wei , Cong Minghua , Wang Kunhua , Song Chunhua , Shi Hanping
Published: December 2022

Purpose

Cachexia has a very high prevalence in patients with cancer, and lacks effective screening tools yet. Global Leadership Initiative on Malnutrition (GLIM) is a novel malnutrition assessment tool, with increased important roles in malnutrition diagnosis for patients with cancer. However, whether GLIM can be used as an effective screening tool remains unknown.

Methods

We performed a multicenter cohort study including 8,478 solid tumor patients from 40 clinical centers throughout China. Cachexia was diagnosed based on the 2011 international cancer cachexia consensus. The receiver operating characteristic curves (ROC) and decision curve analysis (DCA) were developed to determine the efficacy and clinical net benefit of GLIM and Patient-Generated Subjective Global Assessment (PG-SGA) in the detection of cancer cachexia, respectively.

Results

According to the consensus guidelines, 1,441 (17.0%) cancer patients were diagnosed with cachexia among 8,478 patients in the present study. The sensitivity of one-step GLIM and two-step GLIM for detecting cachexia were 100 and 88.8%, respectively, while that of PG-SGA was 86.2%. The accuracies of one-step GLIM and two-step GLIM reached 67.4 and 91.3%, which were higher than that of PG-SGA (63.1%). The area under the curves (AUCs) of one-step GLIM (0.835) and two-step GLIM (0.910) were higher than PG-SGA (0.778) in patients with cancer. The DCA also revealed that two-step GLIM had better clinical effect than PG-SGA between 20-50% threshold probabilities.

Conclusion

GLIM could be used as an effective tool in screening cancer cachexia, two-step GLIM criteria show more accurate while one-step GLIM criteria is more sensitive.

Trial registration

ChiCTR1800020329.
Machine learning-based normal tissue complication probability model for predicting albumin-bilirubin (ALBI) grade increase in hepatocellular carcinoma patients
Authors: Prayongrat Anussara , Srimaneekarn Natchalee , Thonglert Kanokporn , Khorprasert Chonlakiet , Amornwichet Napapat , Alisanant Petch , Shirato Hiroki , Kobashi Keiji , Sriswasdi Sira
Published: December 2022

Purpose:

The aim of this study was to develop a normal tissue complication probability model using a machine learning approach (ML-based NTCP) to predict the risk of radiation-induced liver disease in hepatocellular carcinoma (HCC) patients.

Materials and methods:

The study population included 201 HCC patients treated with radiotherapy. The patients’ medical records were retrospectively reviewed to obtain the clinical and radiotherapy data. Toxicity was defined by albumin-bilirubin (ALBI) grade increase. The normal liver dose-volume histogram was reduced to mean liver dose (MLD) based on the fraction size-adjusted equivalent uniform dose (2 Gy/fraction and α/β = 2). Three types of ML-based classification models were used, a penalized logistic regression (PLR), random forest (RF), and gradient-boosted tree (GBT) model. Model performance was compared using the area under the receiver operating characteristic curve (AUROC). Internal validation was performed by 5-fold cross validation and external validation was done in 44 new patients.

Results:

Liver toxicity occurred in 87 patients (43.1%). The best individual model was the GBT model using baseline liver function, liver volume, and MLD as inputs and the best overall model was an ensemble of the PLR and GBT models. An AUROC of 0.82 with a standard deviation of 0.06 was achieved for the internal validation. An AUROC of 0.78 with a standard deviation of 0.03 was achieved for the external validation. The behaviors of the best GBT model were also in good agreement with the domain knowledge on NTCP.

Conclusion:

We propose the methodology to develop an ML-based NTCP model to estimate the risk of ALBI grade increase.
Levels of HBV RNA in chronic HBV infected patients during first-line nucleos(t)ide analogues therapy
Authors: Jiang Bei , Dai Qinghai , Liu Yamin , Yu Guangxin , Mi Yuqiang
Published: December 2022

Background

Serum HBV RNA has been considered a potential biomarker in monitoring the prognosis of chronic hepatitis B (CHB). However, Real-life cohort studies on the profile of HBV RNA in chronic HBV infected patients during first-line nucleos(t)ide analogues (NAs) are lacking. We aimed to investigate HBV RNA dynamic pattern and clinical value chronic HBV infected patients under NA therapy.

Methods

HBV RNA and clinical assessments were measured in 82 treatment-naïve chronic HBV infected patients. These enrolled patients were categorized into HBeAg-positive chronic HBV infected (n = 53) and HBeAg-negative chronic HBV infected (n = 29). Of these, there were 59, 46, and 30 chronic HBV infected patients completed the follow-up clinical assessments at 12, 24, and 48 weeks of NAs therapy, respectively.

Results

In treatment-naïve patients, there was a positive correlation between HBV RNA and HBV DNA, HBsAg (r = 0.602 and 0.502. P < 0.05). The median level of HBV DNA was higher than HBV RNA by 1.64 log10 copies/mL. The mean level of serum HBV RNA was 4.62 (IQR: 3.05–5.82) log10 copies/mL at baseline, and the median level of HBV RNA was 2.88 (IQR: 0–4.67), 2.71 (IQR: 0–4.22), and 2.96 (IQR: 0–4.32) log10 copies/mL at week 12, 24, and 48, respectively. HBV RNA showed a positive linear correlation with HBV DNA at 12, 24, and 48 weeks of NA treatment (r = 0.640, 0.715, and 0.656 respectively, P < 0.05). In patients who were treated 48 weeks NAs, 67% had quantifiable HBV RNA while only 37% had quantifiable HBV DNA.

Conclusion

HBV RNA has signature profiles in different stages of chronic HBV infected patients receiving first-line NAs. During antiviral treatment, HBV RNA can still monitor the virus activity in patients whose serum HBV DNA cannot be detected.
MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation
Authors: Wu Yang , Wang Yichun , Yao Hanhui , Li Heng , Meng Fanzheng , Li Qidong , Lin Xiansheng , Liu Lianxin
Published: December 2022

Background

Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. Some glycolytic enzymes such as PKM2, the dominant pyruvate kinase in cancer cells, have been shown to engage in non-glycolytic functions that contribute to tumor metabolism. However, the precise mechanisms are not completely understood.

Methods

The role of MNX1-AS1 in hepatocellular carcinoma progression was assessed both in vitro and in vivo. Northern blotting, RNA pulldown, mass spectrometry, RNA-binding protein immunoprecipitation, ChIP, luciferase reporter assays, RNA FISH and immunofluorescence staining were used to explore the detail molecular mechanism of MNX1-AS1 in hepatocellular carcinoma (HCC).

Results

Here we dissect how MNX1-AS1, a long non-coding RNA (lncRNA), reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the cell nucleus. We found that MNX1-AS1 expression was frequently overexpressed in HCC-derived cell lines and tissues compared to their normal hepatic cell counterparts, a finding consistent with its status as pan-cancer expressed lncRNA. In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. In response to EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, GLUT1 and PDK1) are upregulated though the coactivator function of PKM2. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in xenograft models, indicative of the significant contribution of MNX1-AS1 to tumorigenic phenotypes. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc.

Conclusions

Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.
Targeting TMEM205 mediated drug resistance in ovarian clear cell carcinoma using oncolytic virus
Authors: Saini Uksha , Smith Brentley Q. , Dorayappan Kalpana Deepa Priya , Yoo Ji Young , Maxwell G. Larry , Kaur Balveen , Konishi Ikuo , O’Malley David , Cohn David E. , Selvendiran Karuppaiyah
Published: December 2022

Background

Ovarian clear cell carcinoma (OCCC) accounts for approximately 8–10% of epithelial ovarian cancers in the United States. Although it is rare, OCCC usually presents with treatment challenges and the overall prognosis is far worse than high grade serous ovarian cancer HGSOC. The objective of this study was to examine the therapeutic relevance of combining oncolytic virus with cisplatin for ovarian cancer clear cell carcinoma (OCCC).

Results

We identified that TMEM205, a recently discovered transmembrane protein, contributes to chemoresistance in OCCC cells via the exosomal pathway. Mechanistically, TMEM205 undergoes ligand-independent constitutive endocytosis and co-localizes with Rab11 to contribute to the late recycling endosomes in a clathrin-independent manner. Further, we observed that oncolytic virus (oHSV) pretreatment followed by treatment with cisplatin decreases TMEM205 expression and sensitizes cells to cisplatin in a synergistic manner in OCCC cells. TMEM205 interacts with glycoprotein-C of oHSV post-infection; both of these proteins undergo ubiquitination and ultimately get shuttled outside the cell via exosomes. Thus, we demonstrate the mechanotransduction pathway of TMEM205-mediated chemoresistance along with targeting this pathway using oHSV and cisplatin as a powerful therapeutic strategy for OCCC. oHSV combination with cisplatin inhibits OCCC tumor growth in vivo in immunodeficient and immunocompetent mice models.

Conclusion

Our results suggest that the combination of oHSV and cisplatin in immunocompetent as well as immune deficient OCCC tumor bearing mice reduces overall tumor burden as well as metastatic disease thereby providing survival benefit. Additionally, the detection of TMEM205 in exosomal cargo early in OCCC development has potential to be exploited as a biomarker.
The central role of the gut in intensive care
Authors: Corriero Alberto , Gadaleta Raffaella Maria , Puntillo Filomena , Inchingolo Francesco , Moschetta Antonio , Brienza Nicola
Published: December 2022

Critically ill patients undergo early impairment of their gut microbiota (GM) due to routine antibiotic therapies and other environmental factors leading to intestinal dysbiosis. The GM establishes connections with the rest of the human body along several axes representing critical inter-organ crosstalks that, once disrupted, play a major role in the pathophysiology of numerous diseases and their complications. Key players in this communication are GM metabolites such as short-chain fatty acids and bile acids, neurotransmitters, hormones, interleukins, and toxins. Intensivists juggle at the crossroad of multiple connections between the intestine and the rest of the body. Harnessing the GM in ICU could improve the management of several challenges, such as infections, traumatic brain injury, heart failure, kidney injury, and liver dysfunction. The study of molecular pathways affected by the GM in different clinical conditions is still at an early stage, and evidence in critically ill patients is lacking. This review aims to describe dysbiosis in critical illness and provide intensivists with a perspective on the potential as adjuvant strategies (e.g., nutrition, probiotics, prebiotics and synbiotics supplementation, adsorbent charcoal, beta-lactamase, and fecal microbiota transplantation) to modulate the GM in ICU patients and attempt to restore eubiosis.
Comparative genomics of Campylobacter jejuni from clinical campylobacteriosis stool specimens
Authors: Djeghout Bilal , Bloomfield Samuel J. , Rudder Steven , Elumogo Ngozi , Mather Alison E. , Wain John , Janecko Nicol
Published: December 2022

Background

Campylobacter jejuni is a pervasive pathogen of major public health concern with a complex ecology requiring accurate and informative approaches to define pathogen diversity during outbreak investigations. Source attribution analysis may be confounded if the genetic diversity of a C. jejuni population is not adequately captured in a single specimen. The aim of this study was to determine the genomic diversity of C. jejuni within individual stool specimens from four campylobacteriosis patients. Direct plating and pre-culture filtration of one stool specimen per patient was used to culture multiple isolates per stool specimen. Whole genome sequencing and pangenome level analysis were used to investigate genomic diversity of C. jejuni within a patient.

Results

A total 92 C. jejuni isolates were recovered from four patients presenting with gastroenteritis. The number of isolates ranged from 13 to 30 per patient stool. Three patients yielded a single C. jejuni multilocus sequence type: ST-21 (n = 26, patient 4), ST-61 (n = 30, patient 1) and ST-2066 (n = 23, patient 2). Patient 3 was infected with two different sequence types [ST-51 (n = 12) and ST-354 (n = 1)]. Isolates belonging to the same sequence type from the same patient specimen shared 12–43 core non-recombinant SNPs and 0–20 frameshifts with each other, and the pangenomes of each sequence type consisted of 1406–1491 core genes and 231–264 accessory genes. However, neither the mutation nor the accessory genes were connected to a specific functional gene category.

Conclusions

Our findings show that the C. jejuni population recovered from an individual patient’s stool are genetically diverse even within the same ST and may have shared common ancestors before specimens were obtained. The population is unlikely to have evolved from a single isolate at the time point of initial patient infection, leading us to conclude that patients were likely infected with a heterogeneous C. jejuni population. The diversity of the C. jejuni population found within individual stool specimens can inform future methodological approaches to attribution and outbreak investigations.
A physics-based source model for real-time tephra-dispersal forecasting for weak eruption plumes
Authors: Ishii Kensuke , Nishijo Akira , Koyaguchi Takehiro , Suzuki Yujiro J.
Published: December 2022

A physics-based model to estimate source conditions for a tephra-dispersal model is developed. The source condition is generally expressed by a distribution of released particles along an eruption plume (referred to as “source magnitude distribution” SMD). The present model (NIKS-1D) calculates the SMD and the column height for given vent conditions (e.g. mass eruption rate and magma properties) on the basis of an eruption column model below the neutral buoyancy level (NBL), a downwind gravity current model around the NBL, and a particle sedimentation model. It quantitatively reproduces the following features of the SMD for typical explosive eruptions: (1) a significant amount of coarse particles are released from the rising eruption column, whereas most of the fine particles are carried to the NBL, (2) in a downwind gravity current, the coarse particles tend to decrease more rapidly with distance from the vent than the fine particles, (3) the SMD from the downwind gravity current decreases with distance more slowly in a strong ambient wind than that in a weak ambient wind, and (4) the SMD from the downwind gravity current for eruptions with large mass eruption rates decreases with distance more slowly than that for eruptions with small eruption rates. NIKS-1D includes a new parameter,$$\mu$$μ, which represents the ratio of the volumetric flux at the source of the downwind gravity current to that of the eruption column model at the NBL. This parameter is determined by the physics of the entrainment process around the connection between the eruption column and the downwind gravity current, and depends on the intensity of eruptions. We propose an empirical formula to calculate the value of$$\mu$$μas a function of the mass eruption rate on the basis of the observation data from two well-studied eruption events. In a real-time tephra-dispersal forecasting system, NIKS-1D estimates the mass eruption rate from the observed plume height, and calculates the SMD from the estimated mass eruption rate as a source conditions for a tephra-dispersal forecasting immediately after an eruption.
On the analytical and numerical study for fractional q-integrodifferential equations
Authors: Ibrahim Amira Abd-Elall , Zaghrout Afaf A. S. , Raslan K. R. , Ali Khalid K.
Published: December 2022

In this paper, we give some basic concepts ofq-calculus that will be needed in this paper. Then, we built the q-nonlocal condition that ensures the solution existence and uniqueness of the fractional q-integrodifferential equation. Also, we introduce the continuous dependence of the solution. We find the numerical solution using the finite-difference-Trapezoidal and the cubic B-spline-Trapezoidal methods. Finally, we give three examples to illustrate the validity of our main results.
WHO Functioning and Disability Disaggregation (FDD11) tool: a reliable approach for disaggregating data by disability
Authors: Lee Lindsay , Kamenov Kaloyan , Fellinghauer Carolina , Sabariego Carla , Chatterji Somnath , Cieza Alarcos
Published: December 2022

Background

There is a global scarcity of good quality disability data, which has contributed to a lack of political will to address the challenges that persons with disabilities face. The current paper proposes a way forward to overcome this gap by demonstrating the psychometric properties of the World Health Organization Functioning and Disability Disaggregation Tool (FDD11) - a brief disability disaggregation instrument that countries can use.

Results

The study demonstrated that FDD11 is a valid and reliable tool. Unidimensionality of the scale produced by each calibration was supported by the factor analysis performed. The analysis indicated good fit of the items, and targeting of the items was deemed to be sufficient. The person separation index was 0.82, indicating good reliability of the final scale.

Conclusion

FDD11 provides a good opportunity to researchers and governments to capture good quality disability data and to disaggregate existing data by disability. The tool can facilitate low- and middle-income countries in their efforts to develop evidenced-based policies to address any barriers faced by persons with disabilities, to monitor the implementation of the Convention on the Rights of Persons with Disabilities and the Sustainable Development Goals, and to take stock of the challenges that still remain.