bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct clinical and somatic mutational features of breast tumors with high-, low-, or non-expressing human epidermal growth factor receptor 2 status
Authors: Zhang Guochun , Ren Chongyang , Li Cheukfai , Wang Yulei , Chen Bo , Wen Lingzhu , Jia Minghan , Li Kai , Mok Hsiaopei , Cao Li , Chen Xiaoqing , Lin Jiali , Wei Guangnan , Li Yingzhi , Zhang Yuchen , Balch Charles M. , Liao Ning 
Published: April 2022

Abstract
Background
HER2-low breast cancers were reported to have distinct clinicopathological characteristics from HER2-zero; however, the difference in their genetic features remains unclear. This study investigated the clinical and molecular features of breast tumors according to HER2 status.

Methods
We analyzed the clinicopathological and genomic data of 523 Chinese women with breast cancer. Genomic data was generated by targeted next-generation sequencing (NGS) of breast tumor samples using a commercial 520 gene panel. The cohort was stratified according to HER2 status as HER2-zero (n = 90), HER2-low (n = 231), and HER2-positive (n = 202) according to their immunohistochemistry and fluorescence in situ hybridization results.

Results
HER2-low breast tumors were enriched with hormone receptor-positive tumors, and who had lower Ki67 expression levels. Genes were differentially mutated across HER2 subgroups. HER2-low tumors had significantly more mutations involved in PI3K-Akt signaling than HER2-positive (p < 0.001) and HER2-zero breast tumors (p < 0.01). HER2-zero tumors had more mutations in checkpoint factors (p < 0.01), Fanconi anemia (p < 0.05), and p53 signaling and cell cycle pathway (p < 0.05) compared to HER2-low breast tumors. Compared with HER2-zero tumors, HER2-low tumors had significantly lower pathological complete response rates after neoadjuvant therapy (15.9% vs. 37.5%, p = 0.042) and proportion of relapsed/progressed patients across follow-up time points (p = 0.031), but had comparable disease-free survival (p = 0.271).

Conclusion
Our results demonstrate the distinct clinical and molecular features and clinical outcomes of HER2-low breast tumors.
Pathogenic variants carrier screening in New Brunswick: Acadians reveal high carrier frequency for multiple genetic disorders
Authors: Robichaud Philippe Pierre , Allain Eric P. , Belbraouet Sarah , Bhérer Claude , Mamelona Jean , Harquail Jason , Crapoulet Stéphanie , Crapoulet Nicolas , Bélanger Mathieu , Ben Amor Mouna 
Published: April 2022

Abstract
Background
Founder populations that have recently undergone important genetic bottlenecks such as French-Canadians and Ashkenazi Jews can harbor some pathogenic variants at a higher carrier rate than the general population, putting them at a higher risk for certain genetic diseases. In these populations, there can be considerable benefit to performing ethnic-based or expanded preconception carrier screening, which can help in the prevention or early diagnosis and management of some genetic diseases. Acadians are descendants of French immigrants who settled in the Atlantic Coast of Canada in the seventeenth century. Yet, the Acadian population has never been investigated for the prevalence/frequency of disease-causing genetic variants.

Methods
An exome sequencing panel for 312 autosomal recessive and 30 X-linked diseases was designed and specimens from 60 healthy participants were sequenced to assess carrier frequency for the targeted diseases.

Results
In this study, we show that a sample population of Acadians in South-East New Brunswick harbor variants for 28 autosomal recessive and 1 X-linked diseases, some of which are significantly more frequent in comparison to reference populations.

Conclusion
Results from this pilot study suggests a need for further investigation of genomic variation in this population and possibly implementation of targeted carrier and neonatal screening programs.
HOXC6 impacts epithelial-mesenchymal transition and the immune microenvironment through gene transcription in gliomas
Authors: Huang Hui , Huo Zhengyuan , Jiao Jiantong , Ji Wei , Huang Jin , Bian Zheng , Xu Bin , Shao Junfei , Sun Jun 
Published: April 2022

Abstract
Background
Gliomas are the most common primary malignant tumours of the central nervous system (CNS). To improve the prognosis of glioma, it is necessary to identify molecular markers that may be useful for glioma therapy. HOXC6, an important transcription factor, is involved in multiple cancers. However, the role of HOXC6 in gliomas is not clear.

Methods
Bioinformatic and IHC analyses of collected samples (n = 299) were performed to detect HOXC6 expression and the correlation between HOXC6 expression and clinicopathological features of gliomas. We collected clinical information from 177 to 299 patient samples and estimated the prognostic value of HOXC6. Moreover, cell proliferation assays were performed. We performed Gene Ontology (GO) analysis and gene set enrichment analysis (GSEA) based on ChIP-seq and public datasets to explore the biological characteristics of HOXC6 in gliomas. RNA-seq was conducted to verify the relationship between HOXC6 expression levels and epithelial-mesenchymal transition (EMT) biomarkers. Furthermore, the tumour purity, stromal and immune scores were evaluated. The relationship between HOXC6 expression and infiltrating immune cell populations and immune checkpoint proteins was also researched.

Results
HOXC6 was overexpressed and related to the clinicopathological features of gliomas. In addition, knockdown of HOXC6 inhibited the proliferation of glioma cells. Furthermore, increased HOXC6 expression was associated with clinical progression. The biological role of HOXC6 in gliomas was primarily associated with EMT and the immune microenvironment in gliomas. High HOXC6 expression was related to high infiltration by immune cells, a low tumour purity score, a high stromal score, a high immune score and the expression of a variety of immune checkpoint genes, including PD-L1, B7-H3 and CLTA-4.

Conclusions
These results indicated that HOXC6 might be a key factor in promoting tumorigenesis and glioma progression by regulating the EMT signalling pathway and might represent a novel immune therapeutic target in gliomas.
Emerging role of circular RNAs in the pathogenesis of ovarian cancer
Authors: Ghafouri-Fard Soudeh , Khoshbakht Tayyebeh , Hussen Bashdar Mahmud , Taheri Mohammad , Samsami Majid 
Published: April 2022

AbstractOvarian cancer is a female malignancy with high fatality-to-case ratio, which is due to late detection of cancer. Understanding the molecular mechanisms participating in these processes would facilitate design of therapeutic modalities and identification of novel tumor markers. Recent investigations have shown contribution of circular RNAs (circRNAs) in the evolution of ovarian cancer. These transcripts are produced through a back-splicing mechanism. The enclosed configuration of circRNAs protects them from degradation and potentiates them as biomarkers. Several circRNAs such as circMUC16, circRNA_MYLK, circRNA-UBAP2, circWHSC1, hsa_circ_0013958, circFGFR3, hsa_circRNA_102958 and circ_0072995 have been found to be up-regulated in this cancer, acting as oncogenes. On the other hand, circ-ITCH, circPLEKHM3, circ_100395, circ_0078607, circATRNL1, circHIPK3, circRHOBTB3, circEXOC6B, circ9119 and CDR1as are among down-regulated circRNAs in ovarian cancer. Expression levels of circCELSR1, circ_CELSR1, circATL2, circNRIP1, circTNPO3 and hsa_circ_0000714 have been shown to affect resistance of ovarian cancer cells to chemotherapy. Moreover, circ_100395, circFGFR3, circ_0000554, circCELSR1, circ-PTK2, circLNPEP, circ-CSPP1, circ_0000745, circ_100395 and circPLEKHM3 have been shown to regulate epithelial-mesenchymal transition and metastatic ability of ovarian cancer cells. In the current review, we explain the roles of circRNAs in the evolution and progression of ovarian cancer.
Strategies comparison in response to the two waves of COVID-19 in the United States and India
Authors: Yang Junyan , Shi Leiyu , Chen Haiqian , Wang Xiaohan , Jiao Jun , Yang Manfei , Liu Meiheng , Sun Gang 
Published: April 2022

Abstract
Background
This study aimed to compare the prevention and control strategies adopted by the United States and India in the COVID-19 outbreak and analyze the effectiveness of their strategies, in order to provide empirical experience for the prevention and control of the epidemic.

Methods
This study extracted official data on COVID-19 from various official websites, summarized the policies in place in the United States and India, and evaluated the effectiveness of their policies.

Results
The United States has adopted a series of mitigation strategies to control the two waves of epidemic, including strengthening virus detection, calling on the people to wear masks and so on. As of May 30, 2021, although the daily new cases there decreased to some extent, the effect was not ideal. The US’s daily new cases ranked fourth and the cumulative number of confirmed cases ranked first in the world. India has adopted containment strategies in the initial stage of the outbreak, making the epidemic relatively stable. In the later stage, India has turned to adopt mitigation strategies. In addition, many factors including the lack of medical resources and premature relaxation measures led to the rapid deterioration of the epidemic situation. As of May 30, 2021, although the daily new cases in India has a downward trend, it ranked first in the world, and the cumulative number of confirmed cases ranked second.

Conclusion
There are differences between the epidemic prevention strategies adopted by the United States and India, especially India’s containment strategies which helped it better control the epidemic in the early stage. However, the epidemic in the two countries is still severe. With the advent of virus mutants and the absence of immune barriers, it is meaningful that the two countries continue to take non-pharmacotherapy intervention measures and accelerate vaccination, according to specific national conditions adopt containment strategies that can control the epidemic more quickly when necessary, and pay attention to the risk of epidemic rebound caused by premature relaxation of epidemic prevention policies.
Anaphylactic reactions in the build-up phase of rush immunotherapy for bee venom allergy in pediatric patients: a single-center experience
Authors: Glaeser Antonia , Müller Christoph , Bode Sebastian 
Published: April 2022

Abstract
Background
Anaphylaxis occurs in up to 3.5% of hymenoptera stings and can be a life-threatening emergency. Venom immunotherapy (VIT) provides excellent protection from further episodes of anaphylaxis and is well tolerated. In this study the frequency of anaphylactic reactions in pediatric patients undergoing rush bee venom immunotherapy was assessed as well as possible risk factors and modified up-dosing schemes are reported.

Methods
19 consecutive pediatric patients, who had previously experienced an anaphylactic reaction following a bee sting and showed IgE-mediated sensitization to bee venom, underwent inpatient rush immunotherapy with bee venom extract. We retrospectively compared serological findings (total IgE, serum tryptase level, sensitization to Api m1, Api m3 and Api m10 bee venom allergens) and possible risk factors between patients who experienced an anaphylactic reaction during immunotherapy and patients who did not.

Results
Three of the included 19 patients (15.8%) developed anaphylactic reactions to rush bee venom immunotherapy, all of them between administration of 40 and 80 µg of bee venom extract. However, all three patients reached the standard maintenance dose of 100 µg of bee venom following a modified VIT schedule without any further complications. Total serum IgE levels as well as Api m3 sensitization levels were significantly higher in patients showing an adverse reaction to bee VIT compared to those who did not experience any complications. There were no statistically significant differences concerning age, pre-existing conditions, type and severity of the initial reaction and Api m1, Api m10 and serum tryptase levels between the two subgroups.

Conclusion
Even if anaphylactic reactions occur during the build-up phase of VIT for bee venom in children and adolescents, venom immunotherapy can and should be continued in most cases.
TLR4 mutation protects neurovascular function and cognitive decline in high-fat diet-fed mice
Authors: Obadia Nathalie , Andrade Giulia , Leardini-Tristão Marina , Albuquerque Letícia , Garcia Celina , Lima Flavia , Daleprane Júlio , Castro-Faria-Neto Hugo C. , Tibiriçá Eduardo , Estato Vanessa 
Published: April 2022

AbstractBackgroundMetabolic syndrome (MS) is defined as a low-grade proinflammatory state in which abnormal metabolic and cardiovascular factors increase the risk of developing cardiovascular disease and neuroinflammation. Events, such as the accumulation of visceral adipose tissue, increased plasma concentrations of free fatty acids, tissue hypoxia, and sympathetic hyperactivity in MS may contribute to the direct or indirect activation of Toll-like receptors (TLRs), specifically TLR4, which is thought to be a major component of this syndrome. Activation of the innate immune response via TLR4 may contribute to this state of chronic inflammation and may be related to the neuroinflammation and neurodegeneration observed in MS. In this study, we investigated the role of TLR4 in the brain microcirculation and in the cognitive performance of high-fat diet (HFD)-induced MS mice.MethodsWild-type (C3H/He) and TLR4 mutant (C3H/HeJ) mice were maintained under a normal diet (ND) or a HFD for 24 weeks. Intravital video-microscopy was used to investigate the functional capillary density, endothelial function, and endothelial–leukocyte interactions in the brain microcirculation. Plasma concentrations of monocyte chemoattractant protein-1 (MCP-1), adipokines and metabolic hormones were measured with a multiplex immunoassay. Brain postsynaptic density protein-95 and synaptophysin were evaluated by western blotting; astrocytic coverage of the vessels, microglial activation and structural capillary density were evaluated by immunohistochemistry.ResultsThe HFD-induced MS model leads to metabolic, hemodynamic, and microcirculatory alterations, as evidenced by capillary rarefaction, increased rolling and leukocyte adhesion in postcapillary venules, endothelial dysfunction, and less coverage of astrocytes in the vessels, which are directly related to cognitive decline and neuroinflammation. The same model of MS reproduced in mice deficient for TLR4 because of a genetic mutation does not generate such changes. Furthermore, the comparison of wild-type mice fed a HFD and a normolipid diet revealed differences in inflammation in the cerebral microcirculation, possibly related to lower TLR4 activation.ConclusionsOur results demonstrate that TLR4 is involved in the microvascular dysfunction and neuroinflammation associated with HFD-induced MS and possibly has a causal role in the development of cognitive decline.
Mutation of KIT in cellular extraskeletal myxoid chondrosarcoma: a case report and literature review
Authors: Wang Chen , You Zhi-Jie , Chen Xiao-Yan , Lin Jie , Wu Yi-Juan 
Published: April 2022

Abstract
Background
Extraskeletal myxoid chondrosarcomas (EMCs) are solid tumors that have been genetically and biologically characterized. Only a few studies have discussed the role of the KIT gene or CD117 expression in EMCs, identified by immunohistochemical (IHC) staining. Herein, we present a novel case of cellular EMC exhibiting an EWSR1-NR4A3 fusion, KIT exon 13 mutations and strong diffuse expression of CD117.

Case presentation
A 69-year-old man presented with a fist-sized tumor on his left shoulder. CT revealed a tumor in the left thoracic and dorsal muscle space. The tumor was completely resected. Histologically, the tumor cells had a nodular structure and infiltrated the peripheral fat and muscle tissues. The tumor cells were uniform in size with round nuclei, well-defined nucleoli and eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for CD117, vimentin, CD56 and NSE and focally expressed desmin; the cells were negative for myogenin, S-100, SYN, INSM1, CD34, STAT6, INI-1, Brachyury, ERG, TLE1, AE1/AE3, WT-1, CD99 and SMA. NGS revealed an EWSR1-NR4A3 fusion and KIT exon 13 mutations. The patient had no further treatment after surgery, and no recurrence or metastasis occurred during the ~ 10 month follow-up period.

Conclusions
Molecular detection is an indispensable technique for diagnosing cellular EMCs. The KIT mutations noted in this case report may offer fresh insights into EMCs treatment options.
Reduction of motorcycle-related deaths over 15 years in a developing country
Authors: Yasin Yasin J. , Eid Hani O. , Alao David O. , Grivna Michal , Abu-Zidan Fikri M. 
Published: April 2022

AbstractBackgroundThere have been major improvements in the trauma system and injury prevention in Al-Ain City. We aimed to study the impact of these changes on the incidence, pattern, injury severity, and outcome of hospitalized motorcycle-related injured patients in Al-Ain City, United Arab Emirates.MethodsThis is a retrospective analysis of two separate periods of prospectively collected data which were retrieved from Al-Ain Hospital Trauma Registry (March 2003 to March 2006 compared with January 2014 to December 2017). All motorcycle-injured patients who were admitted to Al-Ain Hospital for more than 24 h or died in the Emergency Department or after hospitalization were studied.ResultsThe incidence of motorcycle injuries dropped by 37.1% over the studied period. The location of injury was significantly different between the two periods (p = 0.02, Fisher's exact test), with fewer injuries occurring at streets/highways in the second period (69.1% compared with 85.3%). The anatomical injury severity of the head significantly increased over time (p = 0.03), while GCS on arrival significantly improved (p < 0.0001), indicating improvements in both prehospital and in-hospital trauma care. The mortality of the patients significantly decreased (0% compared with 6%,p = 0.002, Fisher's exact test).ConclusionsThe incidence of motorcycle injuries in our city dropped by almost 40% over the last 15 years. There was a significant reduction in the mortality of hospitalized motorcycle-injured patients despite increased anatomical severity of the head injuries. This is attributed to improvements in the trauma care system, including injury prevention, and both prehospital and in-hospital trauma care.
Integrated analysis of single-cell and bulk RNA sequencing data reveals a pan-cancer stemness signature predicting immunotherapy response
Authors: Zhang Zhen , Wang Zi-Xian , Chen Yan-Xing , Wu Hao-Xiang , Yin Ling , Zhao Qi , Luo Hui-Yan , Zeng Zhao-Lei , Qiu Miao-Zhen , Xu Rui-Hua 
Published: April 2022

Abstract
Background
Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in cancer therapy, only a limited fraction of patients benefit from it. Cancer stemness can be the potential culprit in ICI resistance, but direct clinical evidence is lacking.

Methods
Publicly available scRNA-Seq datasets derived from ICI-treated patients were collected and analyzed to elucidate the association between cancer stemness and ICI response. A novel stemness signature (Stem.Sig) was developed and validated using large-scale pan-cancer data, including 34 scRNA-Seq datasets, The Cancer Genome Atlas (TCGA) pan-cancer cohort, and 10 ICI transcriptomic cohorts. The therapeutic value of Stem.Sig genes was further explored using 17 CRISPR datasets that screened potential immunotherapy targets.

Results
Cancer stemness, as evaluated by CytoTRACE, was found to be significantly associated with ICI resistance in melanoma and basal cell carcinoma (both P < 0.001). Significantly negative association was found between Stem.Sig and anti-tumor immunity, while positive correlations were detected between Stem.Sig and intra-tumoral heterogenicity (ITH) / total mutational burden (TMB). Based on this signature, machine learning model predicted ICI response with an AUC of 0.71 in both validation and testing set. Remarkably, compared with previous well-established signatures, Stem.Sig achieved better predictive performance across multiple cancers. Moreover, we generated a gene list ranked by the average effect of each gene to enhance tumor immune response after genetic knockout across different CRISPR datasets. Then we matched Stem.Sig to this gene list and found Stem.Sig significantly enriched 3% top-ranked genes from the list (P = 0.03), including EMC3, BECN1, VPS35, PCBP2, VPS29, PSMF1, GCLC, KXD1, SPRR1B, PTMA, YBX1, CYP27B1, NACA, PPP1CA, TCEB2, PIGC, NR0B2, PEX13, SERF2, and ZBTB43, which were potential therapeutic targets.

Conclusions
We revealed a robust link between cancer stemness and immunotherapy resistance and developed a promising signature, Stem.Sig, which showed increased performance in comparison to other signatures regarding ICI response prediction. This signature could serve as a competitive tool for patient selection of immunotherapy. Meanwhile, our study potentially paves the way for overcoming immune resistance by targeting stemness-associated genes.
PTH (1-34) enhances the therapeutic effect of bone marrow mesenchymal stem cell-derived exosomes by inhibiting proinflammatory cytokines expression on OA chondrocyte repair in vitro
Authors: Shao Li-tao , Luo Liang , Qiu Jie-hong , Deng David Y. B. 
Published: April 2022

Abstract
Background
The effects of bone marrow mesenchymal stem cells (BMSCs) during the treatment of cartilage damage have been proven to be attributed to paracrine mechanisms, particularly the effect of exosomes. Exosomes from different batches are inhomogeneous, and different treatment effects are observed between samples. The purpose of this research was to find more effective and homogeneous exosomes for the repair of chondrocytes in osteoarthritis (OA). We observed the potential effects and possible mechanisms of exosomes derived from parathyroid hormone (PTH) (1-34)-preconditioned BMSCs (ExoPTH) in the alleviation of OA.

Materials and methods
Exosomes derived from BMSCs (ExoBMSC) and ExoPTH were isolated by differential centrifugation. Primary rat chondrocytes were used to establish the OA model by interleukin 1 beta (IL-1β) in vitro. The effects of these two types of exosomes on OA chondrocyte proliferation, migration, apoptosis, and extracellular matrix formation were measured and compared. We observed changes in IL-2, TNF-α, and IL-6 levels via Western blotting (WB), and quantitative real-time PCR (qRT–PCR).

Results
We successfully extracted ExoBMSC and ExoPTH and established an IL-1β-induced OA model in primary chondrocytes from rats. Our study showed that IL-2, TNF-α, and IL-6 levels increased significantly in OA chondrocytes; however, both ExoBMSC and ExoPTH reduced the levels of IL-2, TNF-α, and IL-6. In addition, ExoPTH exhibited stronger anti-inflammatory effects. ExoPTH had a more marked effect on proliferation, migration, and production of the extracellular matrix (Col-II) in OA chondrocytes than ExoBMSC at 24 h.

Conclusion
ExoPTH increased the migration, proliferation, and chondral matrix formation of OA chondrocytes in vitro. In OA chondrocyte therapy, the potential mechanism of ExoPTH might involve the inhibition of production of proinflammatory cytokines. Although the two types of exosomes had some similar effects, most effects of ExoPTH were better than those of ExoBMSC, so ExoPTH may have a better ability to alleviate OA.