bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

AbstractAbsent 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

AbstractAs 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

Abstract
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

AbstractThe 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.