bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sp1 and C/EBP are necessary to activate the lactoferrin gene promoter during myeloid differentiation
Authors: Khanna-Gupta Arati , Zibello Theresa , Simkevich Carl , Rosmarin Alan G. , Berliner Nancy 
Published: October 2019

AbstractIn this study, we sought to identify factors responsible for the positive modulation of lactoferrin (LF), a neutrophil-specific, secondary-granule protein gene. Initial reporter gene transfection assays indicated that the first 89 base pairs of the LF promoter are capable of directing myeloid-specific LF gene expression. The presence of a C/EBP site flanked by 2 Sp1 sites within this segment of the LF promoter prompted us to investigate the possible role of these sites in LF expression. Cotransfection studies of LF-89luc plasmid with increasing concentrations of a C/EBP expression vector in myeloid cells resulted in a linear transactivation of luciferase reporter activity. Electrophoretic mobility shift assays found that the C/EBP site is recognized by C/EBP and that both LF Sp1 binding sites bind the Sp1 transcription factor specifically in myeloid cells. Mutation of either Sp1 site markedly reduced activity of the LF-89luc plasmid in myeloid cells, and neither Sp1 mutant plasmid was transactivated by a C/EBP expression plasmid to the same extent as wild-type LF-89luc. We also transfected LF-89luc into Drosophila Schneider cells, which do not express endogenous Sp1, and demonstrated up-regulation of luciferase activity in response to a cotransfected Sp1 expression plasmid, as well as to a C/EBP expression plasmid. Furthermore, cotransfection of LF-89luc plasmid simultaneously with C/EBP and Sp1 expression plasmids resulted in an increase in luciferase activity greater than that induced by either factor alone. Taken together, these observations indicate a functional interaction between C/EBP and Sp1 in mediating LF expression.
Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins
Authors: Konopleva Marina , Tari Ana M. , Estrov Zeev , Harris David , Xie Zhong , Zhao Shourong , López-Berestein Gabriel , Andreeff Michael 
Published: October 2019

Abstract
The antiapoptotic proteins, Bcl-2 and Bcl-XL, are expressed in most cases of acute myeloid leukemia (AML) and may contribute to drug resistance in AML. We tested the hypothesis that down-regulation of Bcl-2 alone by antisense oligodeoxynucleotides (Bcl-2-AS) induces apoptosis, even in the presence of other antiapoptotic genes. We tested Bcl-2-AS in myeloid leukemic HL-60 cells, in Bcl-2 and Bcl-XL overexpressing HL-60-DOX cells, and in primary AML samples. Down-regulation of Bcl-2 by Bcl-2-AS reduced the viability of HL-60 cells and, less effectively, HL-60-DOX cells and increased ara-C cytotoxicity in both cell lines. Incubation of primary AML blasts with Bcl-2-AS decreased Bcl-2 expression in CD34+ blast cells after induction of apoptosis and enhancement of ara-C cytotoxicity in 11 of 19 primary AML samples. In 8 samples in which Bcl-2-AS did not induce apoptosis, baseline Bcl-2 levels were found to be strikingly high. The expression of other antiapoptotic proteins (Bcl-XL, Bag-1, A1, and Mcl-1) did not prevent Bcl-2-AS–induced apoptosis. Bcl-2-AS also inhibited colony formation of AML progenitor cells. Low concentrations of Bcl-2-AS induced significant increases in S-phase cells (P = .04). Results establish Bcl-2 as a critical target for AS strategies in AML in which the baseline levels predict response to Bcl-2-AS. Bcl-2 exerts both antiapoptotic and antiproliferative functions in AML. Because early normal hematopoietic stem cells do not express Bcl-2, Bcl-2-AS therapy should be highly selective for AML cells.
Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells
Authors: Withers Barbara , Blyth Emily , Clancy Leighton E. , Yong Agnes , Fraser Chris , Burgess Jane , Simms Renee , Brown Rebecca , Kliman David , Dubosq Ming-Celine , Bishop David , Sutrave Gaurav , Ma Chun Kei Kris , Shaw Peter J. , Micklethwaite Kenneth P. , Gottlieb David J. 
Published: October 2019

Key Points
Partially HLA-matched third-party CMV-specific T cells provide long-term viral control in HSCT patients with resistant CMV infection. Viral control occurs in the setting of recovery of CD8+ terminally differentiated effector T cells.
A novel method to generate T-cell receptor–deficient chimeric antigen receptor T cells
Authors: Kamiya Takahiro , Wong Desmond , Png Yi Tian , Campana Dario 
Published: October 2019

Key PointsNewly designed PEBLs prevent surface expression of T-cell receptor in T cells without affecting their function. Combined with chimeric antigen receptors, PEBLs can rapidly generate powerful antileukemic T cells without alloreactivity.
Rates and predictors of switching to tenofovir alafenamide-containing ART in a nationwide cohort
Authors:   the Swiss HIV Cohort Study, Surial Bernard , Cavassini Matthias , Calmy Alexandra , Fehr Jan , Stöckle Marcel , Bernasconi Enos , Roth Bianca , Fux Christoph A. , Kovari Helen , Furrer Hansjakob , Rauch Andri , Wandeler Gilles 
Published: October 2019

AbstractBackgroundTenofovir alafenamide (TAF)-containing combinations were introduced in Switzerland after October 2016 and are recommended over tenofovir disoproxil fumarate (TDF) in patients with osteoporosis or impaired renal function.MethodsWe included all participants of the Swiss HIV Cohort Study on TDF-containing antiretroviral therapy with follow-up visits after January 2016. We determined the proportion of switches from TDF to TAF overall, and among patients with risk factors for TDF toxicity, including osteoporosis, impaired renal function or marked proteinuria. We used multivariable logistic regression to explore predictors of switching from TDF to TAF.ResultsWe included 5′012 patients, of whom 652 (13.0%) had risk factors for TDF toxicity. A switch from TDF to TAF was undertaken in 2′796 (55.8%) individuals overall, and in 465 (71.3%) with risk factors. Predictors of switching to TAF were male sex (adjusted odds ratio 1.27, 95% confidence interval 1.07–1.50), age > 50 years (1.43, 1.23–1.66) and the presence of risk factors for TDF toxicity (2.21, 1.77–2.75). In contrast, patients with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based single-pill regimen (0.11, 0.09–0.13), those treated in non-tertiary care centers (0.56, 0.46–0.70), as well as those with CD4 cell counts below 500/μL (0.77, 0.66–0.90) and with chronic hepatitis C infection (0.66, 0.54–0.80) were most likely to stay on TDF.ConclusionsOver 50% of patients on TDF-containing therapy, including the majority of patients at risk for TDF toxicity, were switched to TAF within two years of its introduction in Switzerland. Individuals on NNRTI-based single-pill regimens were most likely to remain on TDF.
Dorsal subscapularis approach for the surgical drainage of subscapularis intramuscular abscess: a case report
Authors: Furuhata Ryogo , Inoue Doji , Kiyota Yasuhiro , Morioka Hideo , Arino Hiroshi 
Published: October 2019

Abstract

Background
Abscess formation in the subscapularis muscle is a rare clinical condition. Few reports are available regarding the treatment methods and surgical approaches for subscapularis intramuscular abscesses. Here, we describe a case of subscapularis intramuscular abscess that was treated successfully via surgical drainage using a new approach, the “dorsal subscapularis approach”.

Case presentation
A 67-year-old woman presented to our hospital with complaints of fever and disturbance of consciousness. Two days prior to visiting our hospital, right shoulder pain and limited range of motion in the shoulder were noted. Cerebrospinal fluid examination and contrast-enhanced computed tomography (CT) imaging on admission revealed a right subscapularis intramuscular abscess with concomitant bacterial meningitis. The patient’s clinical symptoms improved after antibiotic administration for 3 weeks, but the right shoulder pain persisted. Contrast-enhanced CT imaging performed after antibiotic administration revealed an abscess in the right shoulder joint space, in addition to a capsule of the abscess in the right subscapularis muscle. We performed open surgical drainage for the abscess, which had spread from the subscapularis muscle to the glenohumeral joint. Using the deltoid-pectoral approach, we detected exudate and infected granulation tissue in the joint cavity. Furthermore, we separated the dorsal side of the subscapularis muscle from the scapula using a raspatory and detected infected granulation tissue in the subscapularis muscle belly. We performed curettage and washed as much as possible. After surgery, antibiotic administration continued for 2 weeks. The patient’s right shoulder pain subsided and CT performed 2 months after surgery revealed no recurrence of infection.

Conclusions
The present case indicated that a subscapularis intramuscular abscess could lead to severe concomitant infections of other organs via the hematogenous route. Thus, early detection and treatment are necessary. Moreover, in this case, surgical drainage using a dorsal subscapularis approach was beneficial to treating the abscess, which had spread from the subscapularis muscle to the glenohumeral joint.
Volumetric characteristics of idiopathic pulmonary fibrosis lungs: computational analyses of high-resolution computed tomography images of lung lobes
Authors: Sul Bora , Flors Lucia , Cassani Joanne , Morris Michael J. , Reifman Jaques , Altes Talissa , Wallqvist Anders 
Published: October 2019

AbstractBackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease involving progressive degeneration of lung capacity. Current diagnosis of IPF heavily relies on visual evaluation of fibrotic features in high-resolution computed tomography (HRCT) images of the lungs. Although the characteristics of this disease have been studied at the molecular and cellular levels, little is known about the mechanical characteristics of IPF lungs inferred from HRCT images. To this end, we performed a pilot study to investigate the radiographic and volumetric characteristics of lungs in subjects with IPF.MethodsWe collected HRCT images of healthy (N = 13) and IPF (N = 9) lungs acquired at breath-holds after full inspiration (expanded state) and full expiration (contracted state). We performed statistical analyses on Hounsfield unit (HU) histograms, lobar volumes (V: lobe volume normalized by the lung volume), and lobar flows (Q: the difference in lobe volume divided by the difference in lung volume between the expanded and contracted states).ResultsParameters characterizing the HU histograms (i.e., mean, median, skewness, and kurtosis) significantly differed between healthy and IPF subjects, for all lobes in both expanded and contracted states. The distribution ofVacross lobes differed significantly between the groups in both states. The distribution ofQalso differed significantly between the groups:Qvalues of the lower lobes for the IPF group were 33% (right) and 22% (left) smaller than those for the healthy group, consistent with the observation that radiographic scores were highest in the lower lung section in IPF. Notably, the root-mean-squared difference (RMSD) ofQ, a measure of distance from the mean value of the healthy group, clearly distinguished the IPF subjects (RMSD ofQ > 1.59) from the healthy group (RMSD ofQ < 0.67).ConclusionThis study shows that lung volume and flow distribution change heterogeneously across the lung lobes of IPF subjects, with reduced capacity in the lower lobes. These volumetric changes may improve our understanding of the pathophysiology in IPF lungs.
Construction of a novel MK-4 biosynthetic pathway in Pichia pastoris through heterologous expression of HsUBIAD1
Authors: Sun Xiaowen , Liu Hui , Wang Peng , wang Li , Ni Wenfeng , Yang Qiang , Wang Han , Tang Hengfang , Zhao Genhai , Zheng Zhiming 
Published: October 2019

AbstractBackgroundWith a variety of physiological and pharmacological functions, menaquinone is an essential prenylated product that can be endogenously converted from phylloquinone (VK1) or menadione (VK3) via the expression ofHomo sapiensUBIAD1 (HsUBIAD1). The methylotrophic yeast,Pichia pastoris, is an attractive expression system that has been successfully applied to the efficient expression of heterologous proteins. However, the menaquinone biosynthetic pathway has not been discovered inP. pastoris.ResultsFirstly, we constructed a novel synthetic pathway inP. pastorisfor the production of menaquinone-4 (MK-4) via heterologous expression ofHsUBIAD1. Then, the glyceraldehyde-3-phosphate dehydrogenase constitutive promoter (PGAP) appeared to be mostsuitable for the expression ofHsUBIAD1 for various reasons. By optimizing the expression conditions ofHsUBIAD1, its yield increased by 4.37 times after incubation at pH 7.0 and 24 °C for 36 h, when compared with that under the initial conditions. We foundHsUBIAD1 expressed in recombinant GGU-23 has the ability to catalyze the biosynthesis of MK-4 when using VK1and VK3as the isopentenyl acceptor. In addition, we constructed a ribosomal DNA (rDNA)-mediated multi-copy expression vector for the fusion expression ofSaGGPPS andPpIDI, and the recombinant GGU-GrIG afforded higher MK-4 production, so that it was selected as the high-yield strain. Finally, the yield of MK-4 was maximized at 0.24 mg/g DCW by improving the GGPP supply when VK3was the isopentenyl acceptor.ConclusionsIn this study, we constructed a novel synthetic pathway inP. pastorisfor the biosynthesis of the high value-added prenylated product MK-4 through heterologous expression ofHsUBIAD1 and strengthened accumulation of GGPP. This approach could be further developed and accomplished for the biosynthesis of other prenylated products, which has great significance for theoretical research and industrial application.
Prognostic value of YKL-40 in solid tumors: a meta-analysis of 41 cohort studies
Authors: Bian Bingxian , Li Li , Yang Junyao , Liu Yi , Xie Guohua , Zheng Yingxia , Zeng Liang , Zeng Junxiang , Shen Lisong 
Published: October 2019

AbstractBackgroundSerum/plasma YKL-40 can be a useful index that is associated with tumor development. However, the prognostic value of serum/plasma YKL-40 in patients with solid tumors is still unclear. We aimed to utilize the existing literature to investigate the prognostic value of serum/plasma YKL-40 in solid tumors.MethodsAn extensive literature search for relevant studies was conducted with the Embase, Medline and Web of Science databases. The effect on survival was measured with the hazard ratio (HR). Then, pooled HRs and 95% confidence intervals (CIs) were calculated using the random and fixed-effects models according to the heterogeneity of the included studies.ResultsThis meta-analysis was based on 41 publications and comprised a total of 7762 patients with solid tumors. The pooled HR showed that elevated serum/plasma YKL-40 was significantly associated with poor OS (HR, 1.44; 95% CI 1.33–1.56). We also found that elevated serum/plasma YKL-40 had significant prognostic effects on OS in various cancer subgroups such as gastrointestinal tumors (HR, 1.37; 95% CI 1.18–1.58), ovarian cancer (HR, 2.27; 95% CI 1.69–3.06), melanoma (HR, 1.77; 95% CI 1.18–2.67), lung cancer (HR, 1.73; 95% CI 1.35–2.23), urologic neoplasms (HR, 1.61; 95% CI 1.08–2.40) and glioblastoma (HR, 1.23; 95% CI 1.07–1.42); in contrast, the prognostic effect of serum/plasma YKL-40 was not statistically significant in breast cancer (HR, 1.07; 95% CI 0.98–1.17).ConclusionsThe available evidence supports the hypothesis that elevated serum/plasma YKL-40 is associated with poor survival in patients with solid tumors and that serum/plasma YKL-40 may serve as a novel prognostic biomarker.
Identification of Cancer–associated metabolic vulnerabilities by modeling multi-objective optimality in metabolism
Authors: Dai Ziwei , Yang Shiyu , Xu Liyan , Hu Hongrong , Liao Kun , Wang Jianghuang , Wang Qian , Gao Shuaishi , Li Bo , Lai Luhua 
Published: October 2019

Abstract

Background
Cancer cells undergo global reprogramming of cellular metabolism to satisfy demands of energy and biomass during proliferation and metastasis. Computational modeling of genome-scale metabolic models is an effective approach for designing new therapeutics targeting dysregulated cancer metabolism by identifying metabolic enzymes crucial for satisfying metabolic goals of cancer cells, but nearly all previous studies neglect the existence of metabolic demands other than biomass synthesis and trade-offs between these contradicting metabolic demands. It is thus necessary to develop computational models covering multiple metabolic objectives to study cancer metabolism and identify novel metabolic targets.

Methods
We developed a multi-objective optimization model for cancer cell metabolism at genome-scale and an integrated, data-driven workflow for analyzing the Pareto optimality of this model in achieving multiple metabolic goals and identifying metabolic enzymes crucial for maintaining cancer-associated metabolic phenotypes. Using this workflow, we constructed cell line-specific models for a panel of cancer cell lines and identified lists of metabolic targets promoting or suppressing cancer cell proliferation or the Warburg Effect. The targets were then validated using knockdown and over-expression experiments in cultured cancer cell lines.

Results
We found that the multi-objective optimization model correctly predicted phenotypes including cell growth rates, essentiality of metabolic genes and cell line specific sensitivities to metabolic perturbations. To our surprise, metabolic enzymes promoting proliferation substantially overlapped with those suppressing the Warburg Effect, suggesting that simply targeting the overlapping enzymes may lead to complicated outcomes. We also identified lists of metabolic enzymes important for maintaining rapid proliferation or high Warburg Effect while having little effect on the other. The importance of these enzymes in cancer metabolism predicted by the model was validated by their association with cancer patient survival and knockdown and overexpression experiments in a variety of cancer cell lines.

Conclusions
These results confirm this multi-objective optimization model as a novel and effective approach for studying trade-off between metabolic demands of cancer cells and identifying cancer-associated metabolic vulnerabilities, and suggest novel metabolic targets for cancer treatment.

Graphical abstract
MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2
Authors: Martínez de Paz Alexia , Khajavi Leila , Martin Hélène , Claveria-Gimeno Rafael , Tom Dieck Susanne , Cheema Manjinder S. , Sanchez-Mut Jose V. , Moksa Malgorzata M. , Carles Annaick , Brodie Nick I. , Sheikh Taimoor I. , Freeman Melissa E. , Petrotchenko Evgeniy V. , Borchers Christoph H. , Schuman Erin M. , Zytnicki Matthias , Velazquez-Campoy Adrian , Abian Olga , Hirst Martin , Esteller Manel , Vincent John B. , Malnou Cécile E. , Ausió Juan 
Published: October 2019

AbstractBackgroundMeCP2—a chromatin-binding protein associated with Rett syndrome—has two main isoforms, MeCP2-E1 and MeCP2-E2, differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest that they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored.ResultsHere, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl-binding domain (MBD) to interact with DNA as well as influencing the turn-over rates, binding dynamics, response to neuronal depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes.ConclusionsOur study supports the idea that Rett syndrome might arise from simultaneous impairment of cellular processes involving non-overlapping functions of MECP2 isoforms. For instance, MeCP2-E1 mutations might impact stimuli-dependent chromatin regulation, while MeCP2-E2 mutations could result in aberrant ribosomal expression. Overall, our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.
Role of neuromedin B and its receptor in the innate immune responses against influenza A virus infection in vitro and in vivo
Authors: Yang Guihong , Huang Huipeng , Tang Mengyao , Cai Zifeng , Huang Cuiqin , Qi Baomin , Chen Ji-Long 
Published: October 2019

Abstract
The peptide neuromedin B (NMB) and its receptor (NMBR) represent a system (NMB/NMBR) of neuromodulation. Here, it was demonstrated that the expression of NMBR in cells or murine lung tissues was clearly upregulated in response to H1N1/PR8 influenza A virus infection. Furthermore, the in vitro and in vivo activities of NMB/NMBR during PR8 infection were investigated. It was observed that A549 cells lacking endogenous NMBR were more susceptible to virus infection than control cells, as evidenced by the increased virus production in the cells. Interestingly, a significant decrease in IFN-α and increased IL-6 expression were observed in these cells. The role of this system in innate immunity against PR8 infection was probed by treating mice with NMB. The NMB-treated mice were less susceptible to virus challenge, as evidenced by increased survival, increased body weight, and decreased viral NP expression compared with the control animals. Additionally, the results showed that exogenous NMB not only enhanced IFN-α expression but also appeared to inhibit the expression of NP and IL-6 in PR8-infected cells and animals. As expected, opposing effects were observed in the NMBR antagonist-treated cells and mice, which further confirmed the effects of NMB. Together, these data suggest that NMB/NMBR may be an important component of the host defence against influenza A virus infection. Thus, these proteins may serve as promising candidates for the development of novel antiviral drugs.