bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials
Authors: Tummala Raj , Abreu Gabriel , Pineda Lilia , Michaels M Alex , Kalyani Rubana N , Furie Richard A , Morand Eric F 
Published: February 2021

ObjectiveIn phase II and III trials, anifrolumab, a human monoclonal antibody that binds type I interferon receptor subunit 1, has shown efficacy in adults with moderate to severe SLE. We evaluated the safety and tolerability of anifrolumab using data pooled from these trials to more precisely estimate the rate and severity of adverse events (AEs).MethodsData were pooled from patients receiving monthly intravenous anifrolumab 300 mg or placebo in MUSE, TULIP-1 and TULIP-2. Key safety endpoints included percentages and exposure-adjusted incidence rates (EAIRs) of patients who experienced AEs, serious AEs (SAEs), AEs leading to discontinuation and AEs of special interest.ResultsDuring treatment, 86.9% of patients receiving anifrolumab 300 mg (n=459) experienced AEs (≥1) versus 79.4% receiving placebo (n=466), and 4.1% versus 5.2% experienced an AE leading to discontinuation of investigational product. SAEs (≥1) were experienced by 11.8% and 16.7% of patients receiving anifrolumab and placebo, respectively (EAIR risk difference (95% CI) −7.2 (−12.5 to –1.9)), including lupus exacerbations classified as SAEs (1.5% and 3%, respectively). Infections occurred in 69.7% and 55.4% of patients receiving anifrolumab and placebo, respectively; difference in reported rates was driven by herpes zoster (HZ) and mild and moderate respiratory (excluding pneumonia) infections. The risk of HZ was increased with anifrolumab versus placebo (6.1% vs 1.3%, respectively; EAIR risk difference (95% CI) 5.4 (2.8 to 8.4)); most HZ events were mild or moderate, cutaneous and resolved without treatment discontinuation. Serious infections occurred in 4.8% and 5.6% of patients receiving anifrolumab and placebo, respectively.ConclusionsIn this pooled analysis of 925 patients with moderate to severe SLE, monthly intravenous anifrolumab 300 mg was generally well tolerated over 52 weeks with an acceptable safety profile. Anifrolumab was associated with an increased incidence of HZ and respiratory tract infections and lower reported rate of SLE worsening as SAEs.
Audit of oxygen administration to achieve a target oxygen saturation range in acutely unwell medical patients
Authors: Harper James , Kearns Nethmi , Bird Grace , McLachlan Robert , Eathorne Allie , Weatherall Mark , Beasley Richard 
Published: February 2021

AbstractPurpose of the studyTo evaluate documentation of a target oxygen saturation (SpO2) range and ability to achieve this range in acutely unwell inpatients.Study designIn this single-centre audit, patients with discharge diagnoses of pneumonia, heart failure and exacerbation of asthma or COPD admitted to Wellington Regional Hospital, New Zealand between 1 June 2019 and 31 August 2019 who received oxygen were identified. In those with a documented target SpO2 range, the proportion of SpO2 measurements in the observation chart which were within, above and below range were determined as well as the maximum and minimum SpO2. Regression analysis was performed to determine whether these outcomes were influenced by the prescribed range, high-dependency care or the number of adjustments to oxygen administration.Results268 admissions were screened. Of the 100 eligible admissions who received oxygen, a target SpO2 range was documented in 62. The mean (SD) proportion of SpO2 measurements within range was 56.2 (30.6)%. A hypercapnic target SpO2 range was associated with a higher probability of an SpO2 above range; multivariate OR 5.34 (95% CI 1.65 to 17.3, p=0.006) and a lower probability of an SpO2 below range; multivariate OR 0.25 (95% CI 0.08 to 0.80) p=0.02. The mean (SD) maximum SpO2 was similar in those with a target range of 92%–96% versus a hypercapnic range; 96.2 (3.0)% and 95.2 (3.4)%, respectively.ConclusionsOxygen prescription and delivery in this clinical setting was suboptimal. SpO2 values above the designated range are common, particularly in patients with a hypercapnic target range.
Role of the IL-33/ST2 axis in cigarette smoke-induced airways remodelling in chronic obstructive pulmonary disease
Authors: Huang Qiong , Li Chen Duo , Yang Yi Ran , Qin Xiao Feng , Wang Jing Jing , Zhang Xin , Du Xiao Nan , Yang Xia , Wang Ying , Li Lun , Mu Mi , Lv Zhe , Cui Ye , Huang Kewu , Corrigan Chris J , Wang Wei , Ying Sun 
Published: February 2021

BackgroundEfficient therapy and potential prophylaxis are confounded by current ignorance of the pathogenesis of airway remodelling and blockade in COPD.ObjectiveTo explore the role of the IL-33/ST2 axis in cigarette smoke (CS) exposure-induced airways remodelling.MethodsC57BL/6, BALB/c andIL-1RL1-/-mice exposed to CS were used to establish an animal surrogate of COPD (air-exposed=5~8, CS-exposed=6~12). Hallmarks of remodelling were measured in mice. Cigarette smoke extract (CSE)-induced proliferation and protein production in vitro by fibroblasts in the presence of anti-interleukin-33 (anti-IL-33) or hST2 antibodies were measured. Expression of IL-33 and ST2 and other remodelling hallmarks were measured, respectively, in bronchoalveolar lavage fluid (BALF) (controls=20, COPD=20), serum (controls=59, COPD=90) and lung tissue sections (controls=11, COPD=7) from patients with COPD and controls.ResultsWild-type mice exposed to CS elevated expression of hallmarks of tissue remodelling in the lungs and also in the heart, spleen and kidneys, which were significantly abrogated in theIL-1RL1-/-mice. Fibroblasts exposed to CSE, compared with control, exhibited early cellular translocation of IL-33, accompanied by proliferation and elevated protein synthesis, all inhabitable by blockade of IL-33/ST2 signalling. Expression of IL-33 and ST2 and hallmarks of tissue remodelling were significantly and proportionally elevated in BALF, serum and tissue samples from patients with COPD.ConclusionsExposure to CS induces remodelling changes in multiple organs. The data support the hypothesis that CS-induced lung collagen deposition is at least partly a result of CS-induced IL-33 translocation and release from local fibroblasts.
Predicting distribution, production, recreational fishing demand, and conservation concern of Indigenous rainbow trout populations based on landscape characteristics
Authors: Cantin Ariane , Farineau Anne , Bender Darren J. , Post John R. 
Published: February 2021

Landscape ecology has mainly been integrated in aquatic science to describe patterns and processes in stream networks, but many lakes are connected through their tributaries and are also impacted by their position and connectivity within the watershed. This information on lake characteristics can be used by inland fisheries managers that oversee large landscapes comprising many waterbodies to predict (i) species composition; (ii) population dynamics and productivity; (iii) recreational fishing pressure; and (iv) overall conservation concern. We developed a methodology to assess these four items for the rainbow trout (Oncorhynchus mykiss) fishery of British Columbia by presenting a case study focused on the Clearwater and North Thompson watersheds using the following: the connectivity of lakes within the stream network to predict rainbow trout presence, stream order and lake area to estimate habitat availability and predict population dynamics and productivity (supply), and travel time from population centres to predict recreational fishing pressure (demand). By incorporating connectivity and environmental proxies of habitat, we explore patterns in population dynamics that can be used by fisheries managers to identify populations sensitive to overfishing or disturbance.
Improving living biomass C-stock loss estimates by combining optical satellite, airborne laser scanning, and NFI data
Authors: Breidenbach Johannes , Ivanovs Janis , Kangas Annika , Nord-Larsen Thomas , Nilsson Mats , Astrup Rasmus 
Published: February 2021

Policy measures and management decisions aimed at enhancing the role of forests in mitigating climate change require reliable estimates of carbon (C)-stock dynamics in greenhouse gas inventories (GHGIs). The aim of this study was to assemble design-based estimators to provide estimates relevant for GHGIs using National Forest Inventory (NFI) data. We improve basic expansion (BE) estimators of living-biomass C-stock loss using only field data, by leveraging with remote sensing auxiliary data in model-assisted (MA) estimators. Our case studies from Norway, Sweden, Denmark, and Latvia covered an area of >70 Mha. Landsat-based forest cover loss (FCL) and one-time wall-to-wall airborne laser scanning (ALS) served as auxiliary data. ALS provided information on the C stock before a potential disturbance indicated by FCL. The use of FCL in MA estimators resulted in considerable efficiency gains, which in most cases were further increased by adding ALS. A doubling of efficiency was possible for national estimates and even larger efficiencies were observed at the subnational level. Average annual estimates were considerably more precise than pooled estimates of the NFI data from all years at once. The combination of remotely sensed and NFI field data yields reliable estimators, which is not necessarily the case when using remotely sensed data without reference observations.
Reconstructing wormhole solutions in curvature based Extended Theories of Gravity
Authors: De Falco Vittorio , Battista Emmanuele , Capozziello Salvatore , De Laurentis Mariafelicia 
Published: February 2021

AbstractStatic and spherically symmetric wormhole solutions can be reconstructed in the framework of curvature based Extended Theories of Gravity. In particular, extensions of the General Relativity, in metric and curvature formalism give rise to modified gravitational potentials, constituted by the classical Newtonian potential and Yukawa-like corrections, whose parameters can be, in turn, gauged by the observations. Such an approach allows to reconstruct the spacetime out of the wormhole throat considering the asymptotic flatness as a physical property for the related gravitational field. Such an argument can be applied for a large class of curvature theories characterising the wormholes through the parameters of the potentials. According to this procedure, possible wormhole solutions could be observationally constrained. On the other hand, stable and traversable wormholes could be a direct probe for this class of Extended Theories of Gravity.
Efficient Designs of Reversible Shift Register Circuits with Low Quantum Cost
Authors: Noorallahzadeh Mojtaba , Mosleh Mohammad 
Published: February 2021

Reversible computations have attracted a lot of attention in recent years due to the ability to reduce energy dissipation that is needed in nanocircuits. The main purpose of designing reversible circuits is to reduce the energy consumption that occurs due to the loss of input bits in irreversible circuits. In this paper, we initially proposed a new [Formula: see text] reversible block and then its quantum realization is given using the Miller et al. method. In the following, an effective reversible design of D flip-flop is introduced using the proposed reversible block. Finally, four types of reversible shift register including serial-in to parallel-out (SIPO), parallel-in to parallel-out (PIPO), parallel-in to serial-out (PISO) and shift counter are proposed using the proposed reversible flip-flop. The evaluation results show that the proposed circuits are superior compared to the existing designs in terms of quantum cost (QC).
Performance of Cotton, Cotton-Polyester, and Polyester-Elastane Fabrics Impregnated with Ultrafine Polymeric Nanoparticles Loaded with Lavender Oil
Authors: Saade H. , de León-Gómez R. Díaz , Treviño M. E. , Rodríguez-Fernández O. S. , Soriano-Corral F. , Borjas J. J. , Castellanos F. , Enríquez-Medrano F. J. , Valdez J. A. , López R. G. 
Published: February 2021

Lavender oil- (LO-) loaded ultrafine nanoparticles (NP) (

diameter
<
50

nm

) of a copolymer were used for impregnating fabrics of cotton, cotton polyester, and polyester-elastane. The copolymer was composed mainly of methyl methacrylate (MMA) units with a low proportion of methacrylic acid (MAA). Moreover, two kinds of NP were used: one containing uncrosslinked copolymer and another one composed of crosslinked material. All the fabrics impregnated with NP of uncrosslinked copolymer keep the aroma up to 25 washes. Under storage at ambient conditions, the fabrics impregnated with NP of either uncrosslinked or crosslinked copolymer emitted aroma for up to almost 60 days. The long duration of aroma emission from fabrics is attributed to ease of the small nanoparticles used in this study of penetrating and staying inside the pores of the fabric fibers.
Hypoxia-Induced Autophagy Enhances Cisplatin Resistance in Human Bladder Cancer Cells by Targeting Hypoxia-Inducible Factor-1α
Authors: Mao Xiawa , Nanzhang  , Xiao Jiaquao , Wu Huifeng , Ding Kefeng 
Published: February 2021

Purpose. To investigate the effect of hypoxia on chemoresistance and the underlying mechanism in bladder cancer cells. Methods. BIU-87 bladder cancer cell line was treated with cisplatin under hypoxic and normoxic conditions and tested using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, and Western blotting. All the data were expressed as

mean
±
standard

error

from three independent experiments and analyzed by multiple

t

-tests. Results. Apoptosis of bladder cancer cells caused by cisplatin was attenuated in hypoxic conditions. Hypoxia enhanced autophagy caused by cisplatin. The autophagy inhibitor and HIF-1α inhibitor can reverse the chemoresistance in hypoxic condition. Apoptosis and autophagy of bladder cancer cells were downregulated by HIF-1α inhibitor YC-1. Hypoxia-induced autophagy enhanced chemoresistance to cisplatin via the HIF-1 signaling pathway. Conclusion. Resistance to cisplatin in BIU-87 bladder cancer cells under hypoxic conditions can be explained by activation of autophagy, which is regulated by HIF-1α-associated signaling pathways. The hypoxia–autophagy pathway may be a target for improving the efficacy of cisplatin chemotherapy in bladder cancer.
Mevalonate Pathway Inhibition Slows Breast Cancer Metastasis via Reduced N-glycosylation Abundance and Branching
Authors: Yu Rosemary , Longo Joseph , van Leeuwen Jenna E. , Zhang Cunjie , Branchard Emily , Elbaz Mohamad , Cescon David W. , Drake Richard R. , Dennis James W. , Penn Linda Z. 
Published: February 2021

Abstract

Aberrant N-glycan Golgi remodeling and metabolism are associated with epithelial–mesenchymal transition (EMT) and metastasis in patients with breast cancer. Despite this association, the N-glycosylation pathway has not been successfully targeted in cancer. Here, we show that inhibition of the mevalonate pathway with fluvastatin, a clinically approved drug, reduces both N-glycosylation and N-glycan-branching, essential components of the EMT program and tumor metastasis. This indicates novel cross-talk between N-glycosylation at the endoplasmic reticulum (ER) and N-glycan remodeling at the Golgi. Consistent with this cooperative model between the two spatially separated levels of protein N-glycosylation, fluvastatin-induced tumor cell death was enhanced by loss of Golgi-associated N-acetylglucosaminyltransferases MGAT1 or MGAT5. In a mouse model of postsurgical metastatic breast cancer, adjuvant fluvastatin treatment reduced metastatic burden and improved overall survival. Collectively, these data support the immediate repurposing of fluvastatin as an adjuvant therapeutic to combat metastatic recurrence in breast cancer by targeting protein N-glycosylation at both the ER and Golgi.

Significance:
These findings show that metastatic breast cancer cells depend on the fluvastatin-sensitive mevalonate pathway to support protein N-glycosylation, warranting immediate clinical testing of fluvastatin as an adjuvant therapy for breast cancer.
Dynamic Regulation of Expression of KRAS and Its Effectors Determines the Ability to Initiate Tumorigenesis in Pancreatic Acinar Cells
Authors: Assi Mohamad , Achouri Younes , Loriot Axelle , Dauguet Nicolas , Dahou Hajar , Baldan Jonathan , Libert Maxime , Fain Jean S. , Guerra Carmen , Bouwens Luc , Barbacid Mariano , Lemaigre Frédéric P. , Jacquemin Patrick 
Published: February 2021

Abstract

Pancreatic acinar cells are a cell type of origin for pancreatic cancer that become progressively less sensitive to tumorigenesis induced by oncogenic Kras mutations after birth. This sensitivity is increased when Kras mutations are combined with pancreatitis. Molecular mechanisms underlying these observations are still largely unknown. To identify these mechanisms, we generated the first CRISPR-edited mouse models that enable detection of wild-type and mutant KRAS proteins in vivo. Analysis of these mouse models revealed that more than 75% of adult acinar cells are devoid of detectable KRAS protein. In the 25% of acinar cells expressing KRAS protein, transcriptomic analysis highlighted a slight upregulation of the RAS and MAPK pathways. However, at the protein level, only marginal pancreatic expression of essential KRAS effectors, including C-RAF, was observed. The expression of KRAS and its effectors gradually decreased after birth. The low sensitivity of adult acinar cells to Kras mutations resulted from low expression of KRAS and its effectors and the subsequent lack of activation of RAS/MAPK pathways. Pancreatitis triggered expression of KRAS and its effectors as well as subsequent activation of downstream signaling; this induction required the activity of EGFR. Finally, expression of C-RAF in adult pancreas was required for pancreatic tumorigenesis. In conclusion, our study reveals that control of the expression of KRAS and its effectors regulates the sensitivity of acinar cells to transformation by oncogenic Kras mutations.

Significance:
This study generates new mouse models to study regulation of KRAS during pancreatic tumorigenesis and highlights a novel mechanism through which pancreatitis sensitizes acinar cells to Kras mutations.
HDAC11 Regulates Glycolysis through the LKB1/AMPK Signaling Pathway to Maintain Hepatocellular Carcinoma Stemness
Authors: Bi Lei , Ren Yidan , Feng Maoxiao , Meng Peng , Wang Qin , Chen Weiping , Jiao Qinlian , Wang Yuli , Du Lutao , Zhou Fuqiong , Jiang Yucui , Chen Feiyan , Wang Chuanxin , Tang Bo , Wang Yunshan 
Published: February 2021

AbstractHepatocellular carcinoma (HCC) contains a subset of cancer stem cells (CSC) that cause tumor recurrence, metastasis, and chemical resistance. Histone deacetylase 11 (HDAC11) mediates diverse immune functions and metabolism, yet little is known about its role in HCC CSCs. In this study, we report that HDAC11 is highly expressed in HCC and is closely related to disease prognosis. Depletion of HDAC11 in a conditional knockout mouse model reduced hepatocellular tumorigenesis and prolonged survival. Loss of HDAC11 increased transcription of LKB1 by promoting histone acetylation in its promoter region, thereby activating the AMPK signaling pathway and inhibiting the glycolysis pathway, which in turn leads to the suppression of cancer stemness and HCC progression. Furthermore, HDAC11 overexpression reduced HCC sensitivity to sorafenib. Collectively, these data propose HDAC11 as a new target for combination therapy in patients with kinase-resistant HCC.Significance:This study finds that HDAC11 suppresses LKB1 expression in HCC to promote cancer stemness, progression, and sorafenib resistance, suggesting the potential of targeting HDAC11 to treat HCC and overcome kinase inhibitor resistance.
Mutations in the IFNγ-JAK-STAT Pathway Causing Resistance to Immune Checkpoint Inhibitors in Melanoma Increase Sensitivity to Oncolytic Virus Treatment
Authors: Nguyen Tan-Trieu , Ramsay LeeAnn , Ahanfeshar-Adams Mozhdeh , Lajoie Mathieu , Schadendorf Dirk , Alain Tommy , Watson Ian R. 
Published: February 2021

Abstract

Purpose:
Next-generation sequencing studies and CRISPR-Cas9 screens have established mutations in the IFNγ-JAK-STAT pathway as an immune checkpoint inhibitor (ICI) resistance mechanism in a subset of patients with melanoma. We hypothesized ICI resistance mutations in the IFNγ pathway would simultaneously render melanomas susceptible to oncolytic virus (OV) therapy.

Experimental Design:
Cytotoxicity experiments were performed with a number of OVs on a matched melanoma cell line pair generated from a baseline biopsy and a progressing lesion with complete JAK2 loss from a patient that relapsed on anti-PD-1 therapy, in melanoma lines following JAK1/2 RNA interference (RNAi) and pharmacologic inhibition and in Jak2 knockout (KO) B16-F10 mouse melanomas. Furthermore, we estimated the frequency of genetic alterations in the IFNγ-JAK-STAT pathway in human melanomas.

Results:
The melanoma line from an anti-PD-1 progressing lesion was 7- and 22-fold more sensitive to the modified OVs, herpes simplex virus 1 (HSV1-dICP0) and vesicular stomatitis virus (VSV-Δ51), respectively, compared with the line from the baseline biopsy. RNAi, JAK1/2 inhibitor studies, and in vivo studies of Jak2 KOs B16-F10 melanomas revealed a significant increase in VSV-Δ51 sensitivity with JAK/STAT pathway inhibition. Our analysis of The Cancer Genome Atlas data estimated that approximately 11% of ICI-naïve cutaneous melanomas have alterations in IFNγ pathway genes that may confer OV susceptibility.

Conclusions:
We provide mechanistic support for the use of OVs as a precision medicine strategy for both salvage therapy in ICI-resistant and first-line treatment in melanomas with IFNγ-JAK-STAT pathway mutations. Our study also supports JAK inhibitor–OV combination therapy for treatment-naïve melanomas without IFN signaling defects.
See related commentary by Kaufman, p. 3278