bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD44 cross-linking increases malignancy of breast cancer via upregulation of p-Moesin
Authors: Hu Song , Shi Xiaoxing , Liu Yiwen , He Yiqing , Du Yan , Zhang Guoliang , Yang Cuixia , Gao Feng 
Published: November 2020

Abstract
Background
CD44 is highly expressed in most cancer cells and its cross-linking pattern is closely related to tumor migration and invasion. However, the underlying molecular mechanism regarding CD44 cross-linking during cancer cell metastasis is poorly understood. Therefore, the purpose of this study was to explore whether disruption of CD44 cross-linking in breast cancer cells could prevent the cells migration and invasion and determine the effects of CD44 cross-linking on the malignancy of the cancer cells.

Methods
The expression of CD44, CD44 cross-linking and Moesin phosphorylation in breast cancer cells was assessed by Western Blot assays. Effects of CD44 cross-linking on tumor metastasis were evaluated by Transwell assay. The effects of CD44 cross-linking disruption on cell viability were assessed using CCK-8 assays. The expression of p-Moesin between normal and breast cancer tissues was examined by immunohistochemical staining.

Results
High expression of CD44 cross-linking was found in invasive breast cancer cells (BT-549 and MDA-MB-231), which is associated with the malignancy of breast cancer. The expressions of ERM complex in a panel of breast cancer cell lines indicate that Moesin and its phosphorylation may play a significant role in cell metastasis. Moesin phosphorylation was inhibited by CD44 de-crosslinking in breast cancer cells and Moesin shRNA knockdown attenuated the promotion of CD44 cross-linking on cell migration and invasion. Finally, immunohistochemistry results demonstrated that p-Moesin was overexpressed in primary and metastatic cancers.

Conclusions
Our study suggested that CD44 cross-linking could elevate p-Moesin expression and further affect migration and invasion of breast cancer cells. These results also indicate that p-Moesin may be useful in future targeted cancer therapy.
Ex vivo infection of murine precision-cut lung tissue slices with Mycobacterium abscessus: a model to study antimycobacterial agents
Authors: Molina-Torres Carmen Amelia , Flores-Castillo Oscar Noé , Carranza-Torres Irma Edith , Guzmán-Delgado Nancy Elena , Viveros-Valdez Ezequiel , Vera-Cabrera Lucio , Ocampo-Candiani Jorge , Verde-Star Julia , Castro-Garza Jorge , Carranza-Rosales Pilar 
Published: November 2020

AbstractBackgroundMultidrug-resistant infections due toMycobacterium abscessusoften require complex and prolonged regimens for treatment. Here, we report the evaluation of a new ex vivo antimicrobial susceptibility testing model using organotypic cultures of murine precision-cut lung slices, an experimental model in which metabolic activity, and all the usual cell types of the organ are found while the tissue architecture and the interactions between the different cells are maintained.MethodsPrecision cut lung slices (PCLS) were prepared from the lungs of wild type BALB/c mice using the Krumdieck®tissue slicer. Lung tissue slices were ex vivo infected with the virulentM. abscessusstrain L948. Then, we tested the antimicrobial activity of two drugs: imipenem (4, 16 and 64 μg/mL) and tigecycline (0.25, 1 and 4 μg/mL), at 12, 24 and 48 h. Afterwards, CFUs were determined plating on blood agar to measure the surviving intracellular bacteria. The viability of PCLS was assessed by Alamar Blue assay and corroborated using histopathological analysis.ResultsPCLS were successfully infected with a virulent strain ofM. abscessusas demonstrated by CFUs and detailed histopathological analysis. The time-course infection, including tissue damage, parallels in vivo findings reported in genetically modified murine models forM. abscessusinfection. Tigecycline showed a bactericidal effect at 48 h that achieved a reduction of > 4log10CFU/mL against the intracellular mycobacteria, while imipenem showed a bacteriostatic effect.ConclusionsThe use of this new organotypic ex vivo model provides the opportunity to test new drugs againstM. abscessus, decreasing the use of costly and tedious animal models.
N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling
Authors: Xu Junjie , Wan Zhe , Tang Minyue , Lin Zhongjie , Jiang Shi , Ji Lin , Gorshkov Kirill , Mao Qijiang , Xia Shunjie , Cen Dong , Zheng Junhao , Liang Xiao , Cai Xiujun 
Published: November 2020

AbstractBackground and aimsAccumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy.MethodsIn vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation.ResultsIn this study, we found that a circular RNA, circRNA-SORE, which is up-regulated insorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/β-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N6-methyladenosine (m6A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models.ConclusionsThis work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC.
Inverse association between triglyceride glucose index and muscle mass in Korean adults: 2008–2011 KNHANES
Authors: Ahn Sung-Ho , Lee Jun-Hyuk , Lee Ji-Won 
Published: November 2020

Abstract
Background
Since sarcopenia is an important risk factor for falls or cardiovascular disease, early detection and prevention of sarcopenia are being increasingly emphasized. Emerging evidence has indicated relationships between sarcopenia, insulin resistance, and inflammation. The triglyceride glucose (TyG) index, a novel surrogate marker of insulin resistance and systemic inflammation, has not yet been shown to be associated with sarcopenia. This study aimed to examine the relationship between the TyG index and muscle mass in Korean adults.

Methods
This study included 15,741 non-diabetic adults over 19 years old using data from the 2008–2011 Korea National Health and Nutrition Examination Survey. Participants were divided into three groups according to tertiles of the TyG index. A low skeletal muscle mass index (LSMI) was defined by the Foundation for the National Institutes of Health Sarcopenia Project criteria. A weighted multivariate logistic regression model was used to analyze relationships between TyG index tertiles and LSMI.

Results
The ORs (95% CIs) for LSMI in the second and third TyG tertiles, compared to the first tertile, were 1.463 (1.131–1.892) and 1.816 (1.394–2.366), respectively, after adjusting for confounding factors. Higher TyG index values were also associated with increased odds of LSMI in adults under 65 years who did not exercise regularly, who consumed less than 30 g of alcohol per day, who did not currently smoke, and who ate less than 1.5 g of protein/kg/day.

Conclusion
The TyG index was significantly and positively associated with LSMI in Korean adults.
Association between the non-HDL-cholesterol to HDL-cholesterol ratio and non-alcoholic fatty liver disease in Chinese children and adolescents: a large single-center cross-sectional study
Authors: Yang Shouxing , Zhong Jinwei , Ye Mengsi , Miao Lei , Lu Guangrong , Xu Changlong , Xue Zhanxiong , Zhou Xinhe 
Published: November 2020

Abstract
Background
The non-HDL-cholesterol to HDL-cholesterol (NHDLC/HDLC) ratio is closely related to a variety of dyslipidemia-related diseases. This study examined the relationship between the NHDLC/HDLC ratio and non-alcoholic fatty liver (NAFLD) in children and adolescents.

Methods
This cross-sectional survey included a total of 7759 eligible Chinese children and adolescents (5692 boys and 2067 girls) who received routine medical examinations. The anthropometric and laboratory data of the subjects were collected. NAFLD was diagnosed by liver ultrasonography. Binary logistic regression analysis was performed on the NHDLC/HDLC ratio, NHDLC, HDLC and NAFLD. Receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic significance of the above parameters for NAFLD.

Results
The total prevalence of NAFLD was 4.36%, and the prevalence in boys was higher than that in girls (5.61% vs. 1.9%, P < 0.001). The prevalence of NAFLD was positively correlated with the NHDLC/HDLC ratio (P < 0.001). The binary logistic regression analysis demonstrated that the OR was 8.61 (95% CI, 5.90–12.57, P < 0.001) in tertile 3 (highest NHDLC/HDLC ratio) compared with tertile 1 (lowest NHDLC/HDLC ratio). After adjustment for age, sex, body mass index (BMI), alanine aminotransferase (ALT), uric acid (UA), total bilirubin (TB), fasting plasma glucose (FPG) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), the OR for tertile 3 (OR = 1.83, 95% CI, 1.04–3.22, P = 0.035) was still significantly higher than that of tertile 1. The area under the curve (AUC) of the NHDLC/HDLC ratio of boys was 0.787, which was significantly greater than NHDLC and HDLC (0.719 and 0.726, P < 0.001). For girls, the AUC of the NHDLC/HDLC ratio was 0.763, which was also significantly greater than NHDLC (0.661, P < 0.001). The cutoff point of the NHDLC/HDLC ratio was 2.475 in boys and 2.695 in girls. In addition, the AUC of the NHDLC/HDLC ratio was 0.761 in subjects with normal ALT levels (ALT ≤40 U/L), which was significantly higher than NHDLC (0.680, P < 0.001) and HDLC (0.724, P = 0.007). For subjects with elevated ALT levels (ALT > 40 U/L), the AUC of the NHDLC/HDLC ratio (0.746) was also significantly greater than NHDLC (0.646, P < 0.001).

Conclusions
The NHDLC/HDLC ratio was positively correlated with NAFLD in Chinese children and adolescents. It may serve as an effective indicator to help identify NAFLD in children and adolescents.
PD-1/PD-L1 expression profiles within intrahepatic cholangiocarcinoma predict clinical outcome
Authors: Tian Lingyu , Ma Jiaqiang , Ma Lijie , Zheng Bohao , Liu Longzi , Song Danjun , Wang Yining , Zhang Zhao , Gao Qiang , Song Kang , Wang Xiaoying 
Published: November 2020

Abstract
Objective
Immunotherapy targeting the programmed cell death protein-1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway has been observed to be efficient in several solid tumors. We aim to investigate the prognostic significance of PD-1/PD-L1 expression profile in intrahepatic cholangiocarcinoma (ICC).

Materials and methods
We investigated the expression of PD-1, PD-L1, CD8+ T cells, and CD68+ macrophages in paired tumor and adjacent normal tissues from 322 ICC patients using tyramide signal amplification (TSA)-based multiplexed immunohistochemistry.

Results
We found that high proportion of tumor-infiltrating CD8+ PD-1High within CD8+ PD-1+ T cells significantly correlated with advanced TNM stage (P = 0.035). ICC patients with high proportion of CD8+ PD-1High in CD8+ PD-1+ had worse postoperative survival than low proportion patients (P = 0.0037), which was an independently prognostic factor for OS (P = 0.025,). The density of CD68+ PD-L1+ significantly and positively correlated with the density of CD8+ PD-1High (P < 0.0001, r = 0.5927). The proportion of CD68+ PD-L1+ within CD68+ ICC was the risk factor for OS and TTR but not an independently factor for prognosis. The CD68+ PD-L1+ macrophages and CD8+ PD-1High T cells may cooperatively play a role in inhibiting anti-tumor immunity.

Conclusion
CD68+ PD-L1+ macrophages and CD8+ PD-1High T cells predict unfavorable prognosis, which could also bring new progress about immune target therapy in ICC research.
Factors affecting the technical efficiency of rural primary health care centers in Hamadan, Iran: data envelopment analysis and Tobit regression
Authors: Mohammadpour Saeed , Javan-Noughabi Javad , Vafaee Najar Ali , Zangeneh Moharram , Yousefi Shaghayegh , Nouhi Mojtaba , Jahangiri Reza 
Published: November 2020

Abstract
Background
Studying and monitoring the efficiency of primary health care centers has a special place in the health system. Although studies have been conducted in the field of efficiency in Iran, few have focused on rural primary health care centers. In addition, previous studies have not used the child mortality rate and Behvarzes as input and output.

Objective
The present study was conducted aimed to estimate the technical efficiency of rural primary health care centers and determinant factors in Hamadan using data envelopment analysis and Tobit regression.

Methods
This is a Longitudinal study of rural primary health care centers in Hamadan province (2002–2016). Data Envelopment Analysis was employed to estimate technical efficiency of sampled health facilities while Panel Tobit Analysis was applied to predict factors associated with efficiency levels. The outputs were child mortality rate under 1 year of age and child mortality rate 1 year to 5 years of age. The input was Behvarzes (rural health workers).

Results
The results of efficiency analysis showed that the average efficiency scores of the centers had a fluctuating trend during the period of the study, but the average performance scores generally decreased in 2016, as compared with 2002. The highest and lowest average performance scores were observed in 2003 (0.78) and 2013 (0.56), respectively. Number of physicians and rural primary healthcare centers per population had a positive statistically significant and the number of midwives and the total fertility per population had a negative statistically significant effect on efficiency.

Conclusions
The findings suggest some level of wastage of health resources in primary health centers. Findings indicate a level of waste of health resources in primary health centers. Behvarz functions in providing primary care services can be considered in the reallocation and optimal use of available resources at the level of rural health centers.
Tyrosine 192 within the SH2 domain of the Src-protein tyrosine kinase p56Lck regulates T-cell activation independently of Lck/CD45 interactions
Authors: Kästle Matthias , Merten Camilla , Hartig Roland , Kaehne Thilo , Liaunardy-Jopeace Ardiyanto , Woessner Nadine M. , Schamel Wolfgang W. , James John , Minguet Susana , Simeoni Luca , Schraven Burkhart 
Published: November 2020

AbstractBackgroundUpon engagement of the T-cell receptor (TCR), the Src-family protein tyrosine kinase p56Lck phosphorylates components of the TCR (e.g. the TCRζ chains), thereby initiating T-cell activation. The enzymatic activity of Lck is primarily regulated via reversible and dynamic phosphorylation of two tyrosine residues, Y394 and Y505. Lck possesses an additional highly conserved tyrosine Y192, located within the SH2 domain, whose role in T-cell activation is not fully understood.MethodsKnock-in mice expressing a phospho-mimetic (Y192E) form of Lck were generated. Cellular and biochemical characterization was performed to elucidate the function of Y192 in primary T cells. HEK 293T and Jurkat T cells were used for in vitro studies.ResultsCo-immunoprecipitation studies and biochemical analyses using T cells from LckY192Eknock-in mice revealed a diminished binding of LckY192Eto CD45 and a concomitant hyperphosphorylation of Y505, thus corroborating previous data obtained in Jurkat T cells. Surprisingly however, in vitro kinase assays showed that LckY192Epossesses a normal enzymatic activity in human and murine T cells. FLIM/FRET measurements employing an LckY192Ebiosensor further indicated that the steady state conformation of the LckY192Emutant is similar to Lckwt. These data suggest that Y192 might regulate Lck functions also independently from the Lck/CD45-association. Indeed, when LckY192Ewas expressed in CD45−/−/Csk−/−non-T cells (HEK 293T cells), phosphorylation of Y505 was similar to Lckwt, but LckY192Estill failed to optimally phosphorylate and activate the Lck downstream substrate ZAP70. Furthermore, LckY19Ewas recruited less to CD3 after TCR stimulation.ConclusionsTaken together, phosphorylation of Y192 regulates Lck functions in T cells at least twofold, by preventing Lck association to CD45 and by modulating ligand-induced recruitment of Lck to the TCR.Major findingsOur data change the current view on the function of Y192 and suggest that Y192 also regulates Lck activity in a manner independent of Y505 phosphorylation.
Diesel exhaust impairs TREM2 to dysregulate neuroinflammation
Authors: Greve Hendrik J. , Mumaw Christen L. , Messenger Evan J. , Kodavanti Prasada R. S. , Royland Joyce L. , Kodavanti Urmila P. , Block Michelle L. 
Published: November 2020

AbstractBackgroundAir pollution has been linked to neurodegenerative diseases, including Alzheimer’s disease (AD), and the underlying neuroimmune mechanisms remain poorly understood. TREM2 is a myeloid cell membrane receptor that is a key regulator of disease-associated microglia (DAM) cells, where loss-of-functionTREM2mutations are associated with an increased risk of AD. At present, the basic function of TREM2 in neuroinflammation is a point of controversy. Further, the impact of air pollution on TREM2 and the DAM phenotype is largely unknown. Using diesel exhaust (DE) as a model of urban air pollution exposure, we sought to address its impact on TREM2 expression, the DAM phenotype, the association of microglia with the neurovasculature, and the role of TREM2 in DE-induced neuroinflammation.MethodsWYK rats were exposed for 4 weeks to DE (0, 50, 150, 500 μg/m3) by inhalation. DE particles (DEP) were administered intratracheally once (600 μg/mouse) or 8 times (100 μg/mouse) across 28 days to male mice (Trem2+/+,Trem2−/−, PHOX+/+, and PHOX−/−).ResultsRats exposed to DE exhibited inverted-U patterns ofTrem2mRNA expression in the hippocampus and frontal cortex, while TREM2 protein was globally diminished, indicating impaired TREM2 expression. Analysis of DAM markersCx3Cr1,Lyz2, andLplin the frontal cortex and hippocampus showed inverted-U patterns of expression as well, supporting dysregulation of the DAM phenotype. Further, microglial-vessel association decreased with DE inhalation in a dose-dependent manner. Mechanistically, intratracheal administration of DEP increasedTnf(TNFα),Ncf1(p47PHOX), andNcf2(p67PHOX) mRNA expression in onlyTrem2+/+mice, whereIl1b(IL-1β) expression was elevated in onlyTrem2−/−mice, emphasizing an important role for TREM2 in DEP-induced neuroinflammation.ConclusionsCollectively, these findings reveal a novel role for TREM2 in how air pollution regulates neuroinflammation and provides much needed insight into the potential mechanisms linking urban air pollution to AD.
K284-6111 alleviates memory impairment and neuroinflammation in Tg2576 mice by inhibition of Chitinase-3-like 1 regulating ERK-dependent PTX3 pathway
Authors: Ham Hyeon Joo , Lee Yong Sun , Yun Jaesuk , Son Dong Ju , Lee Hee Pom , Han Sang-Bae , Hong Jin Tae 
Published: November 2020

Abstract
Background
Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms. We have previously demonstrated that the 2-({3-[2-(1-cyclohexene-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), the inhibitor of CHI3L1, has the inhibitory effect on memory impairment in Αβ infusion mouse model and on LPS-induced neuroinflammation in the murine BV-2 microglia and primary cultured astrocyte.

Methods
In the present study, we investigated the inhibitory effect of K284-6111 on memory dysfunction and neuroinflammation in Tg2576 transgenic mice, and a more detailed correlation of CHI3L1 and AD. To investigate the effects of K284-6111 on memory dysfunction, we administered K284-6111 (3 mg/kg, p.o.) daily for 4 weeks to Tg2576 mice, followed by behavioral tests of water maze test, probe test, and passive avoidance test.

Results
Administration of K284-6111 alleviated memory impairment in Tg2576 mice and had the effect of reducing the accumulation of Aβ and neuroinflammatory responses in the mouse brain. K284-6111 treatment also selectively inactivated ERK and NF-κB pathways, which were activated when CHI3L1 was overexpressed, in the mouse brain and in BV-2 cells. Web-based gene network analysis and our results of gene expression level in BV-2 cells showed that CHI3L1 is closely correlated with PTX3. Our result revealed that knockdown of PTX3 has an inhibitory effect on the production of inflammatory proteins and cytokines, and on the phosphorylation of ERK and IκBα.

Conclusion
These results suggest that K284-6111 could improve memory dysfunction by alleviating neuroinflammation through inhibiting CHI3L1 enhancing ERK-dependent PTX3 pathway.
CCN3 is dynamically regulated by treatment and disease state in multiple sclerosis
Authors: Naughton Michelle , Moffat Jill , Eleftheriadis George , de la Vega Gallardo Nira , Young Andrew , Falconer John , Hawkins Kristen , Pearson Ben , Perbal Bernard , Hogan Andrew , Moynagh Paul , Loveless Sam , Robertson Neil P. , Gran Bruno , Kee Rachael , Hughes Stella , McDonnell Gavin , Howell Owain , Fitzgerald Denise C. 
Published: November 2020

Abstract
Background
Multiple sclerosis (MS) is an immune-mediated disease that damages myelin in the central nervous system (CNS). We investigated the profile of CCN3, a known regulator of immune function and a potential mediator of myelin regeneration, in multiple sclerosis in the context of disease state and disease-modifying treatment.

Methods
CCN3 expression was analysed in plasma, immune cells, CSF and brain tissue of MS patient groups and control subjects by ELISA, western blot, qPCR, histology and in situ hybridization.

Results
Plasma CCN3 levels were comparable between collective MS cohorts and controls but were significantly higher in progressive versus relapsing-remitting MS and between patients on interferon-β versus natalizumab. Higher body mass index was associated with higher CCN3 levels in controls as reported previously, but this correlation was absent in MS patients. A significant positive correlation was found between CCN3 levels in matched plasma and CSF of MS patients which was absent in a comparator group of idiopathic intracranial hypertension patients. PBMCs and CD4+ T cells significantly upregulated CCN3 mRNA in MS patients versus controls. In the CNS, CCN3 was detected in neurons, astrocytes and blood vessels. Although overall levels of area immunoreactivity were comparable between non-affected, demyelinated and remyelinated tissue, the profile of expression varied dramatically.

Conclusions
This investigation provides the first comprehensive profile of CCN3 expression in MS and provides rationale to determine if CCN3 contributes to neuroimmunological functions in the CNS.
Caring for patients in mental health services during COVID-19 outbreak in China
Authors: Hou Ruihua , Yang Limin , Tang Zhen , Chen Teng 
Published: November 2020

AbstractThis article reflects on some radical changes made in mental health services in China which include the implementation of the initial triage system and the special isolation ward, the early screening and testing for both patients and staff, the smaller teams working on rotating shifts on-site, and the adequate provision of PPE. These measures would be of great value as a reference to the effective delivery of mental health services in other countries through this pandemic.