bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of the Effects of Repeat‐Dose Dabrafenib on the Single‐Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate)
Authors: Nebot Noelia , Won Christina S. , Moreno Victor , Muñoz‐Couselo Eva , Lee Dung‐Yang , Gasal Eduard , Bouillaud Emmanuel 
Published: May 2021

AbstractDabrafenib is an oral BRAF kinase inhibitor approved for the treatment of various BRAF V600 mutation–positive solid tumors. In vitro observations suggesting cytochrome P450 (CYP) 3A induction and organic anion transporting polypeptide (OATP) inhibition prompted us to evaluate the effect of dabrafenib 150 mg twice daily on the pharmacokinetics of midazolam 3 mg (CYP3A substrate) and rosuvastatin 10 mg (OATP1B1/1B3 substrate) in a clinical phase 1, open‐label, fixed‐sequence study in patients with BRAF V600 mutation–positive tumors. Repeat dabrafenib dosing resulted in a 2.56‐fold increase in rosuvastatin maximum observed concentration (Cmax), an earlier time to Cmax, but only a 7% increase in area under the concentration‐time curve from time 0 (predose) extrapolated to infinite time. Midazolam Cmax and AUC extrapolated to infinite time decreased by 47% and 65%, respectively, with little effect on time to Cmax. No new safety findings were reported. Exposure of drugs that are CYP3A4 substrates is likely to decrease when coadministered with dabrafenib. Concentrations of medicinal products that are sensitive OATP1B1/1B3 substrates may increase during the absorption phase.
Rational Design and Effective Control of Gold‐Based Bimetallic Electrocatalyst for Boosting CO2 Reduction Reaction: A First‐Principles Study
Authors: Guo Chen , Zhang Tian , Lu Xiaoqing , Wu Chi‐Man Lawrence 
Published: May 2021

AbstractElectrochemical CO2 reduction reaction (CO2RR) is an effective strategy converting CO2 to value‐added products. Au is regarded as an efficient catalyst for electrochemical reduction of CO2 to CO, and the introduction of Pd can tune CO2RR properties due to its strong affinity to CO. Herein, Au−Pd bimetallic electrocatalysts with different metal ratio were firstly investigated on CO2RR mechanism by using density functional theory. The Au monolayer over Pd substrate and single Pd atom on Au(111) were found to show better CO2RR selectivity against hydrogen evolution reaction (HER). Based on this, various single‐atom catalysts on Au(111) and core–shell models with top Au monolayer were designed to study their CO2RR performance. The results indicated that Pt, Cu, and Rh substrates below Au monolayer could enhance the activity and selectivity for CO production compared to pure Au, in which the limiting potential reduced from −0.74 to −0.63, −0.69, and −0.71 V, respectively. The single Pd embedded on Au(111) could adjust the adsorption strength, which provided an effective site to receive and further reduce CO to CH3OH and CH4 at a low limiting potential of −0.61 V, and also avoided catalyst poisoning due to the over‐strengthened CO adsorption caused by high Pd proportion on the surface. In addition, the adsorption energy of COOH was observed as a better CO2RR reactivity descriptor than the common CO adsorption when establishing scaling relationship, which could avoid the fitting error caused by intermediate physisorption of CO.
4‐phenylbutyric acid promotes hepatocellular carcinoma via initiating cancer stem cells through activation of PPAR‐α
Authors: Chen Shu‐Zhen , Ling Yan , Yu Le‐Xing , Song Yu‐Ting , Chen Xiao‐Fei , Cao Qi‐Qi , Yu Han , Chen Can , Tang Jiao‐Jiao , Fan Zhe‐Cai , Miao Yu‐Shan , Dong Ya‐Ping , Tao Jun‐Yan , Monga Satdarshan P.S. , Wen Wen , Wang Hong‐Yang 
Published: May 2021

AbstractBackground and aims4‐phenylbutyric acid (4‐PBA) is a low molecular weight fatty acid that is used in clinical practice to treat inherited urea cycle disorders. In previous reports, it acted as a chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown.Methods4‐PBA was administered alone or in combination with diethylnitrosamine to investigate its long‐term effect on liver tumorigenesis. The role of 4‐PBA in oncogene‐induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co‐expressed with hMet and β‐catenin point mutation (S45Y) was also observed. RNA‐seq and PCR array were used to screen the pathways and genes involved. In vitro and in vivo studies were conducted to explore the effect of 4‐PBA on liver and validate the underlying mechanism.Results4‐PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b‐Fzd5 mediating β‐catenin signaling. Peroxisome proliferator‐activated receptors (PPAR)‐α induced by 4‐PBA was responsible for the activation of β‐catenin signaling. Thus, intervention of PPAR‐α reversed 4‐PBA‐induced initiation of LCSCs and HCC development in vivo. Further study revealed that 4‐PBA could not only upregulate the expression of PPAR‐α transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR‐α expression predicted poor prognosis in HCC patients.Conclusions4‐PBA could upregulate PPAR‐α to initiate LCSCs by activating β‐catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor‐promoting effect of 4‐PBA under HCC‐inducing environment.
Deubiquitinase USP35 modulates ferroptosis in lung cancer via targeting ferroportin
Authors: Tang Zheng , Jiang Wanli , Mao Ming , Zhao Jinping , Chen Jiakuan , Cheng Nitao 
Published: May 2021

AbstractBackgroundFerroptosis is essential to regulate tumor growth and serves as a promising therapeutic target to lung cancer. Ubiquitin‐specific protease 35 (USP35) belongs to the deubiquitinases family that is associated with cell proliferation and mitosis. In this research, we aim to elucidate the potential role and molecular basis of USP35 in lung cancer.MethodsLung cancer cells were infected with lentiviral vectors to silence or overexpress USP35. Cell viability, colony formation, lipid reactive oxygen species production, intracellular iron metabolism, and other ferroptotic markers were detected. The role of USP35 on ferroptosis and tumor progression were also tested in mouse tumor xenograft models in vivo.ResultsUSP35 was abundant in human lung cancer tissues and cell lines. USP35 knockdown promoted ferroptosis, and inhibited cell growth, colony formation, and tumor progression in lung cancer cells. USP35 overexpression did not affect tumorigenesis and ferroptosis under basal conditions, but reduced erastin/RSL3‐triggered iron disturbance and ferroptosis, thereby facilitating lung cancer cell growth and tumor progression. Further studies determined that USP35 directly interacted with ferroportin (FPN) and functioned as a deubiquitinase to maintain its protein stability. More importantly, we observed that USP35 knockdown sensitized lung cancer cells to cisplatin and paclitaxel chemotherapy.ConclusionUSP35 modulates ferroptosis in lung cancer via targeting FPN, and it is a promising therapeutic target to lung cancer.
FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression
Authors: Miao Lei , Zhuo Zhenjian , Tang Jue , Huang Xiaomei , Liu Jiabin , Wang Hai‐Yun , Xia Huimin , He Jing 
Published: May 2021

AbstractNeuroblastoma (NB) is the most common and deadliest pediatric solid tumor. Targeting and reactivating tumor‐associated macrophages (TAMs) is necessary for reversing immune suppressive state and stimulating immune defense to exert tumoricidal function. However, studies on the function and regulation of TAMs in NB progression are still limited. Fatty acid binding protein 4 (FABP4) in TAMs was correlated with advanced clinical stages and unfavorable histology of NB. FABP4‐mediated macrophages increased migration, invasion, and tumor growth of NB cells. Mechanically, FABP4 could directly bind to ATPB to accelerate ATPB ubiquitination in macrophages. The consequently decreased ATP levels could deactivate NF‐κB/RelA‐IL1α pathway, which subsequently results in macrophages reprogrammed to an anti‐inflammatory phenotype. We also demonstrated that FABP4‐enhanced migration and invasion were significantly suppressed by IL1α blocking antibody. Furthermore, circulating FABP4 was also associated with the clinical stages of NB. Our findings suggest that FABP4‐mediated macrophages may promote proliferation and migration phenotypes in NB cells through deactivating NF‐κB‐IL1α pathway by ubiquitinating ATPB. This study reveals the pathologic and biologic role of FABP4‐mediated macrophages in NB development and exhibits a novel application of targeting FABP4 in macrophages for NB treatment.
Alzheimer's disease: An evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies
Authors: Slater Cody , Wang Qi 
Published: May 2021

AbstractAlzheimer's disease (AD) poses a significant global health concern over the next several decades. Multiple hypotheses have been put forth that attempt to explain the underlying pathophysiology of AD. Many of these are briefly reviewed here, but to‐date no disease‐altering therapy has been achieved. Despite this, recent work expanding on the role of noradrenergic system dysfunction in both the pathogenesis and symptomatic exacerbation of AD has shown promise. The role norepinephrine (NE) plays in AD remains complicated but pre‐tangle tau has consistently been shown to arise in the locus coeruleus (LC) of patients with AD decades before symptom onset. The current research reviewed here indicates NE can facilitate neuroprotective and memory‐enhancing effects through β adrenergic receptors, while α2Aadrenergic receptors may exacerbate amyloid toxicity through a contribution to tau hyperphosphorylation. AD appears to involve a disruption in the balance between these two receptors and their various subtypes. There is also a poorly characterized interplay between the noradrenergic and cholinergic systems. LC deterioration leads to maladaptation in the remaining LC‐NE system and subsequently inhibits cholinergic neuron function, eventually leading to the classic cholinergic disruption seen in AD. Understanding AD as a dysfunctional noradrenergic system, provides new avenues for the use of advanced neural stimulation techniques to both study and therapeutically target the earliest stages of neuropathology. Direct LC stimulation and non‐invasive vagus nerve stimulation (VNS) have both demonstrated potential use as AD therapeutics. Significant work remains, though, to better understand the role of the noradrenergic system in AD and how electroceuticals can provide disease‐altering treatments.
Positive regulation of PFKFB3 by PIM2 promotes glycolysis and paclitaxel resistance in breast cancer
Authors: Lu Chao , Qiao Pengyun , Sun Yonghong , Ren Chune , Yu Zhenhai 
Published: May 2021

AbstractBackgroundBreast cancer (BC) is one of the most common female malignancies in the world. Chemotherapeutic resistance is the major cause of BC therapy failure, leading to tumor recurrence and metastasis. Studies have illustrated the close relationship between glycolysis and BC progression and drug resistance. The key glycolysis regulator, PFKFB3 makes a difference during BC progression and drug resistance. However, the mechanism remains to be unknown.MethodsMass spectrometry analyses were used to found that PIM2 was a potential new binding protein of PFKFB3. Co‐immunoprecipitated and western blot were used to verify the interaction between PIM2 and PFKFB3 in BC and the molecular mechanism by which PIM2 phosphorylates PFKFB3 in regulating the protein function. PFKFB3 mutant forms were used to demonstrate the need for PFKFB3 in BC drug resistance.ResultsWe identified that PIM2 is a new binding protein of PFKFB3. We used biochemical methods to determine that PIM2 can directly bind and change the phosphorylation of PFKFB3 at Ser478 to enhance PFKFB3 protein stability through the ubiquitin‐proteasome pathway. Importantly, phosphorylation of PFKFB3 at Ser478 promoted glycolysis, BC cell growth, and paclitaxel resistance together with PIM2 in vitro and in vivo.ConclusionOur study demonstrates that PIM2 mediates PFKFB3 phosphorylation thus regulates glycolysis and paclitaxel resistance to promote tumor progression in BC and provides preclinical evidence for targeting PFKFB3 as a new strategy in BC treatment to battle paclitaxel resistance.
Copy number and transcriptome alterations associated with metastatic lesion response to treatment in colorectal cancer
Authors: Gambaro Karen , Marques Maud , McNamara Suzan , Couetoux du Tertre Mathilde , Diaz Zuanel , Hoffert Cyrla , Srivastava Archana , Hébert Steven , Samson Benoit , Lespérance Bernard , Ko Yoo‐Joung , Dalfen Richard , St‐Hilaire Eve , Sideris Lucas , Couture Felix , Burkes Ronald , Harb Mohammed , Camlioglu Errol , Gologan Adrian , Pelsser Vincent , Constantin André , Greenwood Celia M.T. , Tejpar Sabine , Kavan Petr , Kleinman Claudia L. , Batist Gerald 
Published: May 2021

AbstractBackgroundTherapeutic resistance is the main cause of death in metastatic colorectal cancer. To investigate genomic plasticity, most specifically of metastatic lesions, associated with response to first‐line systemic therapy, we collected longitudinal liver metastatic samples and characterized the copy number aberration (CNA) landscape and its effect on the transcriptome.MethodsLiver metastatic biopsies were collected prior to treatment (pre, n = 97) and when clinical imaging demonstrated therapeutic resistance (post, n = 43). CNAs were inferred from whole exome sequencing and were correlated with both the status of the lesion and overall patient progression‐free survival (PFS). We used RNA sequencing data from the same sample set to validate aberrations as well as independent datasets to prioritize candidate genes.ResultsWe identified a significantly increased frequency gain of a unique CN, in liver metastatic lesions after first‐line treatment, on chr18p11.32 harboring 10 genes, including TYMS, which has not been reported in primary tumors (GISTIC method and test of equal proportions, FDR‐adjusted p = 0.0023). CNA lesion profiles exhibiting different treatment responses were compared and we detected focal genomic divergences in post‐treatment resistant lesions but not in responder lesions (two‐tailed Fisher's Exact test, unadjusted p ≤ 0.005). The importance of examining metastatic lesions is highlighted by the fact that 15 out of 18 independently validated CNA regions found to be associated with PFS in this study were only identified in the metastatic lesions and not in the primary tumors.ConclusionThis investigation of genomic‐phenotype associations in a large colorectal cancer liver metastases cohort identified novel molecular features associated with treatment response, supporting the clinical importance of collecting metastatic samples in a defined clinical setting.
Loss of m6A demethylase ALKBH5 promotes post‐ischemic angiogenesis via post‐transcriptional stabilization of WNT5A
Authors: Zhao Yongchao , Hu Jingjing , Sun Xiaolei , Yang Kun , Yang Lebing , Kong Lingqiu , Zhang Beijian , Li Fuhai , Li Chaofu , Shi Bei , Hu Kai , Sun Aijun , Ge Junbo 
Published: May 2021

AbstractBackgroundPost‐ischemic angiogenesis is critical for blood flow recovery and ischemic tissue repair. N6‐methyladenosine (m6A) plays essential roles in numerous biological processes. However, the impact and connected mechanism of m6A on post‐ischemic angiogenesis are not fully understood.MethodsAlkB homolog 5 (ALKBH5) was screened out among several methyltransferases and demethylases involved in dynamic m6A regulation. Cardiac microvascular endothelial cells (CMECs) angiogenesis and WNT family member 5A (WNT5A) stability were analyzed upon ALKBH5 overexpression with adenovirus or knockdown with small interfering RNAs in vitro. The blood flow recovery, capillary, and small artery densities were evaluated in adeno‐associated virus (AAV)‐ALKBH5 overexpression or ALKBH5 knockout (KO) mice in a hind‐limb ischemia model. The same experiments were conducted to explore the translational value of transient silencing of ALKBH5 with adenovirus.ResultsALKBH5 was significantly upregulated in hypoxic CMECs and led to a global decrease of m6A level. ALKBH5 overexpression further reduced m6A level in normoxic and hypoxic CMECs, impaired proliferation, migration, and tube formation only in hypoxic CMECs. Conversely, ALKBH5 knockdown preserved m6A levels and promoted angiogenic phenotypes in hypoxic but not in normoxic CMECs. Mechanistically, ALKBH5 regulated WNT5A expression through post‐transcriptional mRNA modulation in an m6A‐dependent manner, which decreased its stability and subsequently impeded angiogenesis in hypoxic CMECs. Furthermore, ALKBH5 overexpression hindered blood flow recovery and reduced CD31 and alpha‐smooth muscle actin expression in hind‐limb ischemia mice. As expected, ALKBH5‐KO mice exhibited improved blood flow recovery, increased capillary, and small artery densities after hind‐limb ischemia, and similar beneficial effects were observed in mice with transient adenoviral ALKBH5 gene silencing.ConclusionWe demonstrate that ALKBH5 is a negative regulator of post‐ischemic angiogenesis via post‐transcriptional modulation and destabilization of WNT5A mRNA in an m6A‐dependent manner. Targeting ALKBH5 may be a potential therapeutic option for ischemic diseases, including peripheral artery disease.
CSF metabolites associate with CSF tau and improve prediction of Alzheimer's disease status
Authors: Dong Ruocheng , Darst Burcu F. , Deming Yuetiva , Ma Yue , Lu Qiongshi , Zetterberg Henrik , Blennow Kaj , Carlsson Cynthia M. , Johnson Sterling C. , Asthana Sanjay , Engelman Corinne D. 
Published: May 2021

AbstractIntroductionCerebrospinal fluid (CSF) total tau (t‐tau) and phosphorylated tau (p‐tau) are biomarkers of Alzheimer's disease (AD), yet much is unknown about AD‐associated changes in tau metabolism and tau tangle etiology.MethodsWe assessed the variation of t‐tau and p‐tau explained by 38 previously identified CSF metabolites using linear regression models in middle‐age controls from the Wisconsin Alzheimer's Disease Research Center, and predicted AD/mild cognitive impairment (MCI) versus an independent set of older controls using metabolites selected by the least absolute shrinkage and selection operator (LASSO).ResultsThe 38 CSF metabolites explained 70.3% and 75.7% of the variance in t‐tau and p‐tau, respectively. Of these, seven LASSO‐selected metabolites improved the prediction ability of AD/MCI versus older controls (area under the curve score increased from 0.92 to 0.97 and 0.78 to 0.93) compared to the base model.DiscussionThese tau‐correlated CSF metabolites increase AD/MCI prediction accuracy and may provide insight into tau tangle etiology.
Cerebrospinal fluid biomarker panel for synaptic dysfunction in Alzheimer's disease
Authors: Nilsson Johanna , Gobom Johan , Sjödin Simon , Brinkmalm Gunnar , Ashton Nicholas J. , Svensson Johan , Johansson Per , Portelius Erik , Zetterberg Henrik , Blennow Kaj , Brinkmalm Ann 
Published: May 2021

AbstractIntroductionSynaptic dysfunction and degeneration is one of the earliest events in Alzheimer's disease (AD) and the best correlate of cognitive decline. Thus, identification and validation of biomarkers reflecting synaptic degeneration to be used as prognostic biomarkers are greatly needed.MethodSolid‐phase extraction and parallel reaction monitoring mass spectrometry were used to quantify 17 synaptic proteins in CSF, in two cross‐sectional studies including AD (n = 52) and controls (n = 37).ResultsIncreased concentrations of beta‐synuclein, gamma‐synuclein, neurogranin, phosphatidylethanolamine‐binding protein 1, and 14‐3‐3 proteins were observed in AD patients compared to controls, while neuronal pentraxin‐2 and neuronal pentraxin receptor were decreased.DiscussionWe have established a method with a novel panel of synaptic proteins as biomarkers of synaptic dysfunction. The results indicate that several of the proteins included in the panel may serve as synaptic biomarkers for AD.
Comparing CSF amyloid‐beta biomarker ratios for two automated immunoassays, Elecsys and Lumipulse, with amyloid PET status
Authors: Willemse Eline A. J. , Tijms Betty M. , van Berckel Bart N. M. , Le Bastard Nathalie , van der Flier Wiesje M. , Scheltens Philip , Teunissen Charlotte E. 
Published: May 2021

AbstractIntroductionWe evaluated for two novel automated biomarker assays how cerebrospinal fluid (CSF) amyloid beta (Aβ)1– 42‐ratios improved the concordance with amyloid positron emission tomography (PET) positivity compared to Aβ1– 42 alone.MethodsWe selected 288 individuals from the Amsterdam Dementia Cohort across the Alzheimer's disease clinical spectrum when they had both CSF and amyloid PET visual read available, regardless of diagnosis. CSF Aβ1– 42, phosphorylated tau (p‐tau), and total tau (t‐tau) were measured with Elecsys and Lumipulse assays, and Aβ1–40 with Lumipulse. CSF cut‐points were defined using receiver operating characteristic (ROC) for amyloid PET positivity.ResultsFor both Elecsys and Lumipulse the p‐tau/Aβ1– 42, Aβ1– 42/Aβ1– 40, and t‐tau/Aβ1– 42 ratios showed similarly good concordance with amyloid PET (Elecsys: 93,90,90%; Lumipulse: 94,92,90%) and were higher than Aβ1– 42 alone (Elecsys 85%; Lumipulse 84%).DiscussionBiomarker ratios p‐tau/Aβ1– 42, Aβ1– 42/Aβ1– 40, t‐tau/Aβ1– 42 on two automated platforms show similar optimal concordance with amyloid PET in a memory clinic cohort.