bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vapour–liquid–liquid and vapour–liquid equilibrium of paraffinic aromatic synthetic naphtha/water blends: Prediction of the number of phases
Authors: Lopez‐Zamora Sandra , Kong Jeonghoon , Escobedo Salvador , de Lasa Hugo 
Published: June 2021

AbstractBitumen is extracted from oil sands using warm water and additives. The resulting bitumen froth is diluted with naphtha in a froth treatment process. Residual naphtha in the aqueous tailings of the froth treatment unit is recovered in a naphtha recovery unit (NRU). It is imperative to maximize the naphtha recovery process to minimize the plant's environmental and economic impact. It is, in this respect, that NRU vapour–liquid–liquid equilibrium data is of significant value. In this work, a paraffinic‐aromatic synthetic naphtha (PASN) with a true boiling point (TBP) similar to that of froth treatment naphtha is used. Water/PASN mixtures are studied using the Soave‐Redlich‐Kwong equation of state with a Kabadi‐Danner modification. The tangent plane distance (TPD) is evaluated as a possible criterion to calculate the number of phases, with its significant shortcomings being established. As well, experimental data obtained in a CREC‐VL‐Cell is observed to display higher solubilities of PASN in water than the ones obtained by HYSYS‐Aspen Plus V9 simulation. To address these issues, a machine learning (ML)‐based phase classification methodology was considered, predicting the number of phases with a 99% recall. This anticipates that ML will be of significant value for faster convergence of the flash split calculations for the naphtha hydrocarbon‐water systems under consideration.
Computational model of silica nanoparticle penetration into tumor spheroids: Effects of methoxy and carboxy PEG surface functionalization and hyperthermia
Authors: Nagesetti Abhignyan , Dulikravich George S. , Orlande Helcio R. B. , Colaco Marcelo J. , McGoron Anthony J. 
Published: June 2021

AbstractDrug delivery to tumors suffers from poor solubility, specificity, diffusion through the tumor micro‐environment and nonoptimal interactions with components of the extracellular matrix and cell surface receptors. Nanoparticles and drug–polymer complexes address many of these problems. However, large size exasperates the problem of slow diffusion through the tumor. Three‐dimensional tumor spheroids are good models to evaluate approaches to mitigate these difficulties and aid in design strategies to improve the delivery of drugs to treat cancer effectively. Diffusion of drug carriers is highly dependent on cell uptake rate parameters (association/dissociation) and temperature. Hyperthermia increases molecular transport and is known to act synergistically with chemotherapy to improve treatment. This study presents a new inverse estimation approach based on Bayesian probability for estimating nanoparticle cell uptake rates from experiments. The parameters were combined with a finite element computational model of nanoparticle transport under hyperthermia conditions to explore its effect on tumor porosity, diffusion and particle binding (association and dissociation) at cell surfaces. Carboxy‐PEG‐silane (cPEGSi) nanoparticles showed higher cell uptake compared to methoxy‐PEG‐silane (mPEGSi) nanoparticles. Simulations were consistent with experimental results from Skov‐3 ovarian cancer spheroids. Amorphous silica (cPEGSi) nanoparticles (58 nm) concentrated at the periphery of the tumor spheroids at 37°C but mild hyperthermia (43°C) increased nanoparticle penetration. Thus, hyperthermia may enhance cancer treatment by improving blood delivery to tumors, enhancing extravasation and penetration into tumors, trigger release of drug from the carrier at the tumor site and possibly lead to synergistic anti‐cancer activity with the drug.
An Open‐Label, Randomized, 2‐Way, Crossover Bioequivalence Study of Cefradine Capsules in Healthy Chinese Volunteers
Authors: Lai Xiuping , Ye Suiwen , Chen Liuhan , Chen Junyi , Zhang Nan , Zhang Yiwen , Wu Junyan , Yao Herui 
Published: June 2021

AbstractThe purpose of this study was to evaluate whether test cefradine capsules and reference cefradine capsules were bioequivalent in healthy Chinese volunteers. An open‐label, randomized, biperiodic, crossover design was used. In each of the 2 study periods (separated by a 1‐week washout period), 250‐mg single doses of either the test or reference cefradine capsule were administered to study participants under fasted and fed conditions. Blood samples were collected at intervals from predose to 8 hours afterward. In the fasting study, the 90% confidence intervals (90%CI) of the Cmax, AUC0‐8h, and AUC0‐∞ for the test and reference preparations were 93.7%‐112.2%, 94.6%‐100.8%, and 94.7%‐100.9%, respectively. In the fed study, the 90%CI of the Cmax, AUC0‐8h, and AUC0‐∞ for the test and reference preparations was 81.0%‐99.1%, 100.5%‐106.3%, and 100.5%‐105.9%, respectively. The results showed that the test cefradine capsules and the reference formulation are bioequivalent under both fasting and fed conditions.
Deregulation of CLTC interacts with TFG, facilitating osteosarcoma via the TGF‐beta and AKT/mTOR signaling pathways
Authors: Shijie Li , Zhen Pan , Kang Qin , Hua Guo , Qingcheng Yang , Dongdong Cheng 
Published: June 2021

AbstractAlthough the treatment of osteosarcoma has improved, the overall survival rate of this common type of osseous malignancies has not changed for four decades. Thus, new targets for better therapeutic regimens are urgently needed. In this study, we found that high expression of clathrin heavy chain (CLTC) was an independent prognostic factor for tumor‐free survival (HzR, 3.049; 95% CI, 1.476–6.301) and overall survival (HzR, 2.469; 95% CI, 1.005–6.067) of patients with osteosarcoma. Down‐regulation of CLTC resulted in tumor‐suppressive effects in vitro and in vivo. Moreover, we found that CLTC was transcriptionally regulated by a transcription factor—specificity protein 1 (SP1), which binds to the CLTC promoter at the −320 to −314‐nt and +167 to +173‐nt loci. Mechanistic investigations further revealed that CLTC elicited its pro‐tumor effects by directly binding to and stabilizing trafficking from the endoplasmic reticulum to the Golgi regulator (TFG). Importantly, overexpression of TFG rescued both the tumor‐suppressive effect and inhibition of the TGF‐β and AKT/mTOR pathways caused by CLTC down‐regulation, which indicated that the activity of CLTC was TFG‐dependent. Immunohistochemistry analysis confirmed that CLTC expression was positively correlated with TFG expression. These findings collectively highlight CLTC as a new prognostic biomarker for patients with osteosarcoma, and the interruption of the SP1/CLTC/TFG axis may serve as a novel therapeutic strategy for osteosarcoma.
IRF2‐mediated upregulation of lncRNA HHAS1 facilitates the osteogenic differentiation of bone marrow‐derived mesenchymal stem cells by acting as a competing endogenous RNA
Authors: Ye Guiwen , Wang Peng , Xie Zhongyu , Li Jinteng , Zheng Guan , Liu Wenjie , Cao Qian , Li Ming , Cen Shuizhong , Li Zhaofeng , Yu Wenhui , Wu Yanfeng , Shen Huiyong 
Published: June 2021

AbstractBackgroundMesenchymal stem cells (MSCs) are the major source of osteoblasts. Long noncoding RNAs (lncRNAs) are abundantly expressed RNAs that lack protein‐coding potential and play an extensive regulatory role in cellular biological activities. However, the regulatory network of lncRNAs in MSC osteogenesis needs further investigation.MethodsQRT‐PCR, western blot, immunofluorescence, and immunohistochemistry assays were used to determine the levels of relevant genes. The osteogenic differentiation capability was evaluated by using Alizarin Red S (ARS) staining, alkaline phosphatase activity assays, hematoxylin & eosin staining or micro‐CT. RNA fluorescence in situ hybridization (FISH) and RNAscope were used to detect HHAS1 expression in cells and bone tissue. A microarray assay was performed to identify differentially expressed microRNAs. RNA immunoprecipitation and RNA pull‐down were used to explore the interactions between related proteins and nucleic acids.ResultsThe level of lncRNA HHAS1 increased during bone marrow‐derived MSC (BMSC) osteogenesis and was positively related to the levels of osteogenic genes and ARS intensity. HHAS1 was located in both the cytoplasm and the nucleus and was expressed in human bone tissue. HHAS1 facilitated BMSC osteogenic differentiation by downregulating miR‐204‐5p expression and enhancing the level of RUNX family transcription factor 2 (RUNX2). In addition, interferon regulatory factor 2 (IRF2) was increased during BMSC osteogenic differentiation and interacted with the promoter of HHAS1, which resulted in the transcriptional activation of HHAS1. Furthermore, IRF2 and HHAS1 helped improve bone defect repair in vivo.ConclusionsOur study identified a novel lncRNA, HHAS1, that facilitates BMSC osteogenic differentiation and proposed a role for the IRF2/HHAS1/miR‐204‐5p/RUNX2 axis in BMSC osteogenesis regulation. These findings help elucidate the regulatory network of BMSC osteogenesis and provide potential targets for clinical application.
Integrated transcriptional‐phenotypic analysis captures systemic immunomodulation following antiangiogenic therapy in renal cell carcinoma patients
Authors: Rinchai Darawan , Verzoni Elena , Huber Veronica , Cova Agata , Squarcina Paola , De Cecco Loris , de Braud Filippo , Ratta Raffaele , Dugo Matteo , Lalli Luca , Vallacchi Viviana , Rodolfo Monica , Roelands Jessica , Castelli Chiara , Chaussabel Damien , Procopio Giuseppe , Bedognetti Davide , Rivoltini Licia 
Published: June 2021

AbstractBackgroundThe combination of immune checkpoint blockade (ICB) with standard therapies is becoming a common approach for overcoming resistance to cancer immunotherapy in most human malignancies including metastatic renal cell carcinoma (mRCC). In this regard, insights into the immunomodulatory properties of antiangiogenic agents may help designing multidrug schedules based on specific immune synergisms.MethodsWe used orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines to elucidate the immunomodulatory effect of the antiangiogenic agent pazopanib in mRCC patients. Nine patients were studied longitudinally over a period of 6 months. We also analyzed transcriptional data from The Cancer Genome Atlas (TCGA) RCC cohort (N = 571) to assess the prognostic implications of our findings. The effect of pazopanib was assessed in vitro on NK cells and T cells. Additionally, myeloid‐derived suppressor (MDSC)‐like cells were generated from CD14+ monocytes transfected with mimics of miRNAs associated with MDSC function in the presence or absence of pazopanib.ResultsPazopanib administration caused a rapid and dramatic reshaping in terms of frequency and transcriptional activity of multiple blood immune cell subsets, with a downsizing of MDSC and regulatory T cells in favor of a strong enhancement in PD‐1 expressing cytotoxic T and Natural Killer effectors. These changes were paired with an increase of the expression of transcripts reflecting activation of immune‐effector functions. This immunomodulation was marked but transient, peaking at the third month of treatment. Moreover, the intratumoral expression level of a MDSC signature (MDSC INT) was strongly associated with poor prognosis in RCC patients. In vitro experiments indicate that the observed immunomodulation might be due to an inhibitory effect on MDSC‐mediated suppression, rather than a direct effect on NK and T cells.ConclusionsThe marked but transient nature of this immunomodulation, peaking at the third month of treatment, provides the rationale for the use of antiangiogenics as a preconditioning strategy to improve the efficacy of ICB.
Treg deficiency‐mediated TH1 response causes human premature ovarian insufficiency through apoptosis and steroidogenesis dysfunction of granulosa cells
Authors: Jiao Xue , Zhang Xiruo , Li Nianyu , Zhang Dunfang , Zhao Shidou , Dang Yujie , Zanvit Peter , Jin Wenwen , Chen Zi‐Jiang , Chen Wanjun , Qin Yingying 
Published: June 2021

AbstractImmune dysregulation has long been proposed as a component of premature ovarian insufficiency (POI), but the underlying mediators and mechanisms remain largely unknown. Here we showed that patients with POI had augmented T helper 1 (TH1) responses and regulatory T (Treg) cell deficiency in both the periphery and the ovary compared to the control women. The increased ratio of TH1:Treg cells was strongly correlated with the severity of POI. In mouse models of POI, the increased infiltration of TH1 cells in the ovary resulted in follicle atresia and ovarian insufficiency, which could be prevented and reversed by Treg cells. Importantly, interferon (IFN) ‐γ and tumor necrosis factor (TNF) ‐α cooperatively promoted the apoptosis of granulosa cells and suppressed their steroidogenesis by modulating CTGF and CYP19A1. We have thus revealed a previously unrecognized Treg cell deficiency‐mediated TH1 response in the pathogenesis of POI, which should have implications for therapeutic interventions in patients with POI.
Molecular and physical technologies for monitoring fluid and electrolyte imbalance: A focus on cancer population
Authors: Bennet Devasier , Khorsandian Yasaman , Pelusi Jody , Mirabella Amy , Pirrotte Patrick , Zenhausern Frederic 
Published: June 2021

AbstractSeveral clinical examinations have shown the essential impact of monitoring (de)hydration (fluid and electrolyte imbalance) in cancer patients. There are multiple risk factors associated with (de)hydration, including aging, excessive or lack of fluid consumption in sports, alcohol consumption, hot weather, diabetes insipidus, vomiting, diarrhea, cancer, radiation, chemotherapy, and use of diuretics. Fluid and electrolyte imbalance mainly involves alterations in the levels of sodium, potassium, calcium, and magnesium in extracellular fluids. Hyponatremia is a common condition among individuals with cancer (62% of cases), along with hypokalemia (40%), hypophosphatemia (32%), hypomagnesemia (17%), hypocalcemia (12%), and hypernatremia (1‐5%). Lack of hydration and monitoring of hydration status can lead to severe complications, such as nausea/vomiting, diarrhea, fatigue, seizures, cell swelling or shrinking, kidney failure, shock, coma, and even death. This article aims to review the current (de)hydration (fluid and electrolyte imbalance) monitoring technologies focusing on cancer. First, we discuss the physiological and pathophysiological implications of fluid and electrolyte imbalance in cancer patients. Second, we explore the different molecular and physical monitoring methods used to measure fluid and electrolyte imbalance and the measurement challenges in diverse populations. Hydration status is assessed in various indices; plasma, sweat, tear, saliva, urine, body mass, interstitial fluid, and skin‐integration techniques have been extensively investigated. No unified (de)hydration (fluid and electrolyte imbalance) monitoring technology exists for different populations (including sports, elderly, children, and cancer). Establishing novel methods and technologies to facilitate and unify measurements of hydration status represents an excellent opportunity to develop impactful new approaches for patient care.
Reduced mTORC1‐signaling in retinal ganglion cells leads to vascular retinopathy
Authors: Jones Iwan , Hägglund Anna‐Carin , Carlsson Leif 
Published: June 2021

AbstractBackgroundThe coordinated wiring of neurons, glia and endothelial cells into neurovascular units is critical for central nervous system development. This is best exemplified in the mammalian retina where interneurons, astrocytes and retinal ganglion cells sculpt their vascular environment to meet the metabolic demands of visual function. Identifying the molecular networks that underlie neurovascular unit formation is an important step towards a deeper understanding of nervous system development and function.ResultsHere, we report that cell‐to‐cell mTORC1‐signaling is essential for neurovascular unit formation during mouse retinal development. Using a conditional knockout approach we demonstrate that reduced mTORC1 activity in asymmetrically positioned retinal ganglion cells induces a delay in postnatal vascular network formation in addition to the production of rudimentary and tortuous vessel networks in adult animals. The severity of this vascular phenotype is directly correlated to the degree of mTORC1 down regulation within the neighboring retinal ganglion cell population.ConclusionsThis study establishes a cell nonautonomous role for mTORC1‐signaling during retinal development. These findings contribute to our current understanding of neurovascular unit formation and demonstrate how ganglion cells actively sculpt their local environment to ensure that the retina is perfused with an appropriate supply of oxygen and nutrients.
Potentiality of miniaturized techniques for the analysis of drugs of abuse
Authors: Fanali Chiara , D'Orazio Giovanni , Gentili Alessandra , Fanali Salvatore 
Published: June 2021

AbstractCapillary electromigration (CE) and liquid chromatographic techniques (CLC/nano‐LC) are miniaturized techniques offering distinct advantages over conventional ones in the field of separation science. Among these, high efficiency, high chromatographic resolution, and use of minute volumes of both mobile phase and sample volumes are the most important. CE and CLC/nano‐LC have been applied to the analysis of many compounds including peptides, proteins, drugs, enantiomers, ions, etc. Over the years, the methods described here have also been used for the analysis of compounds of clinical, forensic, and toxicological interest. In this review article, the main features of the mentioned techniques are summarized. Their potentiality for the analysis of drugs of abuse are discussed. Some selected applications in this field in the period of 2015–present are also reported.
Immunomodulatory Effects of Lenvatinib Plus Anti–Programmed Cell Death Protein 1 in Mice and Rationale for Patient Enrichment in Hepatocellular Carcinoma
Authors: Torrens Laura , Montironi Carla , Puigvehí Marc , Mesropian Agavni , Leslie Jack , Haber Philipp K. , Maeda Miho , Balaseviciute Ugne , Willoughby Catherine E. , Abril‐Fornaguera Jordi , Piqué‐Gili Marta , Torres‐Martín Miguel , Peix Judit , Geh Daniel , Ramon‐Gil Erik , Saberi Behnam , Friedman Scott L. , Mann Derek A. , Sia Daniela , Llovet Josep M. 
Published: June 2021

Background and Aims
Lenvatinib is an effective drug in advanced HCC. Its combination with the anti‐PD1 (programmed cell death protein 1) immune checkpoint inhibitor, pembrolizumab, has generated encouraging results in phase Ib and is currently being tested in phase III trials. Here, we aimed to explore the molecular and immunomodulatory effects of lenvatinib alone or in combination with anti‐PD1.

Approach and Results
We generated three syngeneic models of HCC in C57BL/6J mice (subcutaneous and orthotopic) and randomized animals to receive placebo, lenvatinib, anti‐PD1, or combination treatment. Flow cytometry, transcriptomic, and immunohistochemistry analyses were performed in tumor and blood samples. A gene signature, capturing molecular features associated with the combination therapy, was used to identify a subset of candidates in a cohort of 228 HCC patients who might respond beyond what is expected for monotherapies. In mice, the combination treatment resulted in tumor regression and shorter time to response compared to monotherapies (P < 0.001). Single‐agent anti‐PD1 induced dendritic and T‐cell infiltrates, and lenvatinib reduced the regulatory T cell (Treg) proportion. However, only the combination treatment significantly inhibited immune suppressive signaling, which was associated with the TGFß pathway and induced an immune‐active microenvironment (P < 0.05 vs. other therapies). Based on immune‐related genomic profiles in human HCC, 22% of patients were identified as potential responders beyond single‐agent therapies, with tumors characterized by Treg cell infiltrates, low inflammatory signaling, and VEGFR pathway activation.

Conclusions
Lenvatinib plus anti‐PD1 exerted unique immunomodulatory effects through activation of immune pathways, reduction of Treg cell infiltrate, and inhibition of TGFß signaling. A gene signature enabled the identification of ~20% of human HCCs that, although nonresponding to single agents, could benefit from the proposed combination.
Streamflow response to native forest restoration in former Eucalyptus plantations in south central Chile
Authors: Lara Antonio , Jones Julia , Little Christian , Vergara Nicolás 
Published: June 2021

AbstractGlobal increases in intensive forestry have raised concerns about forest plantation effects on water, but few studies have tested the effects of plantation forest removal and native forest restoration on catchment hydrology. We describe results of a 14‐year paired watershed experiment on ecological restoration in south central Chile which documents streamflow response to the early stages of native forest restoration, after clearcutting of plantations of exotic fast‐growing Eucalyptus, planting of native trees, and fostering natural regeneration of native temperate rainforest species. Precipitation, streamflow, and vegetation were measured starting in 2006 in four small (3 to 5 ha) catchments with Eucalyptus globulus plantations and native riparian buffers in the Valdivian Coastal Reserve. Mean annual precipitation is 2500 mm, of which 11% occurs in summer. Streamflow increased, and increases persisted, throughout the first 9 years of vigorous native forest regeneration (2011 to 2019). Annual streamflow increased by 40% to >100% in most years and >150% in fall and summer of some years. Streamflow was 50% to 100% lower than before treatment in two dry summers. Base flow increased by 28% to 87% during the restoration period compared to pre‐treatment, and remained elevated in later years despite low summer precipitation. Overall, these findings indicate that removal of Eucalyptus plantations immediately increased streamflow, and native forest restoration gradually restored deep soil moisture reservoirs that sustain base flow during dry periods, increasing water ecosystem services. To our knowledge this is the first study to assess catchment streamflow response to native forest restoration in former forest plantations. Therefore, the results of this study are relevant to global efforts to restore native forest ecosystems on land currently intensively managed with fast‐growing forest plantations and may inform policy and decision‐making in areas experiencing a drying trend associated with climate change.