bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carbon monoxide: raising awareness of the silent killer in the emergency department
Authors: Malik Fahad Siddique , Ghazal Asswad Randa , Clarke Simon 
Published: June 2022

BackgroundCarbon monoxide (CO) is an odourless gas produced by the incomplete combustion of carbon containing materials. CO poisoning causes a range of symptoms of which headache is the most common, occurring in up to 90% of patients. An audit in the Emergency Department at University Hospital Aintree, Liverpool, UK found a lack of clinical awareness among healthcare professionals (HCPs) with CO exposure being considered in only 0.8% of patients presenting with non-traumatic headache. This Quality Improvement Project (QIP) aimed to increase this consideration to 50% of presentations.MethodsThree separate sequential Plan Do Study Act (PDSA) cycles were instigated. Interventions involved verbal reminders to frontline HCPs (cycle 1), using strategically placed CO posters (cycle 2) and finally designing and introducing a CO sticker education scheme (cycle 3). These stickers, highlighting the approved CO COMA acronym, were placed in patient notes to serve as a physical reminder for HCPs when seeing patients. Rapid cycle sequencing was used with each cycle lasting 2 weeks. Patient notes were analysed for evidence that the HCP considered a diagnosis of CO.ResultsAn average of 61 patients were included in each PDSA cycle. Given baseline findings, each cycle demonstrated positive results with CO awareness being considered in 1.7% and 10.0% of patients with non-traumatic headache following cycles 1 and 2, respectively. The final PDSA cycle demonstrated significant increase in consideration of CO to 42.1% of non-traumatic headache presentations.ConclusionThis QIP demonstrated that even small interventions can lead to significant change in awareness of CO exposure. Implementation of a CO sticker education scheme is a feasible way of increasing awareness among emergency care professionals and serves as a low-cost, easy to use, transferable and sustainable solution to address the lack of CO awareness in acute emergency settings. Importantly, this serves to promote improved patient safety.
T cell repertoire in peripheral blood as a potential biomarker for predicting response to concurrent cetuximab and nivolumab in head and neck squamous cell carcinoma
Authors: Wang Xuefeng , Muzaffar Jameel , Kirtane Kedar , Song Feifei , Johnson Matthew , Schell Michael J , Li Jiannong , Yoder Sean J , Conejo-Garcia Jose R , Guevara-Patino Jose A , Bonomi Marcelo , Bhateja Priyanka , Rocco James W , Steuer Conor E , Saba Nabil F , Chung Christine H 
Published: June 2022

BackgroundT cell receptor (TCR) signaling profile is a fundamental property that underpins both adaptive and innate immunity in the host. Despite its potential clinical relevance, the TCR repertoire in peripheral blood has not been thoroughly explored for its value as an immunotherapy efficacy biomarker in head and neck squamous cell carcinoma (HNSCC). The purpose of the present study is to characterize and compare the TCR repertoire in peripheral blood mononuclear cells (PBMC) from patients with HNSCC treated with the combination of cetuximab and nivolumab.MethodsWe used the immunoSEQ assay to sequence the TCR beta (TCR-B) chain repertoire from serially obtained PBMC at baseline and during the treatments from a total of 41 patients who received the combination (NCT03370276). Key TCR repertoire metrics, including diversity and clonality, were calculated and compared between patients with different therapy responses and clinical characteristics (eg, human papillomavirus (HPV) status and smoking history). Patient survival outcomes were compared according to patient groups stratified by the TCR-B clonotyping. To confirm the observed patterns in TCR spectrum, samples from patients who achieved complete response (CR) and partial response (PR) were further profiled with the immunoSEQ deep resolution assay.ResultsOur data indicated that the patients who achieved CR and PR had an increased TCR sequence diversity in their baseline samples, this tendency being more pronounced in HPV-negative patients or those with a smoking history. Notably, the CR/PR group had the lowest proportion of patients with oligoclonal TCR clones (2 out of 8 patients), followed by the stable disease group (9 out of 20 patients) and lastly the progressive disease group (7 out of 10 patients). An overall trend toward favorable patient survival was also observed in the polyclonal group. Finally, we reported the shared TCR clones across patients within the same response group, as well as the shared clones by aligning immunoSEQ reads with TCR data retrieved from The Cancer Genome Atlas- head and neck squamous cell carcinoma (TCGA-HNSC) cohort.ConclusionsOur data suggest that, despite the great clinical heterogeneity of HNSCC and the limited responders in the present cohort, the peripheral TCR repertoires from pretreatment PBMC may be developed as biomarkers for the benefit of immunotherapy in HNSCC.
Data-directed search for new physics based on symmetries of the SM
Authors: Birman Mattias , Nachman Benjamin , Sebbah Raphael , Sela Gal , Turetz Ophir , Bressler Shikma 
Published: June 2022

AbstractWe propose exploiting symmetries (exact or approximate) of the Standard Model (SM) to search for physics Beyond the Standard Model (BSM) using the data-directed paradigm (DDP). Symmetries are very powerful because they provide two samples that can be compared without requiring simulation. Focusing on the data, exclusive selections which exhibit significant asymmetry can be identified efficiently and marked for further study. Using a simple and generic test statistic which compares two matrices already provides good sensitivity, only slightly worse than that of the profile likelihood ratio test statistic which relies on the exact knowledge of the signal shape. This can be exploited for rapidly scanning large portions of the measured data, in an attempt to identify regions of interest. We also demonstrate that weakly supervised Neural Networks could be used for this purpose as well.
Towards a Reliable Text Summarization Evaluation Metric Using Predictive Models
Authors: Zhao Bo , Lui Yui Man 
Published: June 2022

With an increasing number of new summarization systems proposed in recent years, an automatic text evaluation metric that can accurately and reliably rate the performance of summarization systems has been a pressing need. However, current automatic text evaluation metrics can only measure one or certain aspects of the quality between two summary texts and do not agree with human judgments consistently. In this paper, we show that combining multiple well-chosen evaluation metrics and training predictive models using human annotated datasets can lead to more reliable evaluation scores than using any individual automatic metric. Our predictive models trained on a human annotated subset of the CNN/DailyMail corpus demonstrate significant improvements (e.g. approximately 25% along coherence dimension) over selected individual metrics. Furthermore, a concise meta-evaluation on automatic metrics is provided along with an analysis of the performance of 12 predictive models. We also investigate the sensitivity of automatic metrics when mixed together for training these models. We have made the code, the instructions for experiment setup, and the trained models available as a tool for comparing and evaluating text summarization systems. a a https://github.com/bzhao2718/ReliableSummEvalReg .
Altered Hsp90 function in cancer: A unique therapeutic opportunity
Authors: Bagatell Rochelle , Whitesell Luke 
Published: June 2022

Abstract
Molecular chaperones or so-called heat shock proteins serve as central integrators of protein homeostasis within cells. In performing this function, they guide the folding, intracellular disposition, and proteolytic turnover of many key regulators of cell growth, differentiation, and survival. Recent data show essential roles for the chaperones in facilitating malignant transformation at the molecular level and support the concept that their altered utilization during oncogenesis is critical to the development of human cancers. The field is evolving rapidly, but it has become apparent that chaperones can serve as biochemical buffers at the phenotypic level for the genetic instability that is characteristic of many human cancers. Chaperone proteins thus allow tumor cells to tolerate the mutation of multiple critical signaling molecules that would otherwise be lethal. Much of the recent progress in understanding the complex role of heat shock proteins in tumorigenesis has been made possible by the discovery of several natural product antitumor antibiotics that selectively inhibit the function of the chaperone Hsp90. These agents have been used as probes to define the biological functions of Hsp90 at the molecular level and to validate it as a novel target for anticancer drug action. One of these agents, 17-allylamino,17-demethoxygeldanamycin (NSC 330507) has begun phase II clinical trials, and several second-generation compounds are now in late preclinical development. The best way to use Hsp90 inhibitors as anticancer agents remains to be defined. Trials accomplished to date, however, serve as proof of principle that Hsp90 function can be modulated pharmacologically without undue toxicity in humans. Given the redundancy and complexity of the signaling pathway abnormalities present in most cancers, the ability of Hsp90 inhibitors to alter the activity of multiple aberrant signaling molecules instead of just one or two (as most current-generation molecular therapeutics have been designed to do) may prove of unique therapeutic benefit.
Biological evaluation of cryptophycin 52 fragment A analogues: Effect of the multidrug resistance ATP binding cassette transporters on antitumor activity
Authors: Al-awar Rima S. , Corbett Thomas H. , Ray James E. , Polin Lisa , Kennedy Joseph H. , Wagner Margaret M. , Williams Daniel C. 
Published: June 2022

Abstract
Cryptophycin 52 (LY355703) is a potent antiproliferative analogue of the marine natural product cryptophycin 1. It has been shown to have a broad range of antitumor activity against human tumor xenografts and murine tumors including tumors resistant to Taxol and Adriamycin. Its mechanism of action involves arresting cells in the G2-M phase of the cell cycle by binding to microtubules and suppressing their dynamics. This 16-membered depsipeptide can be divided into four major subunits or fragments (A–D). We reported previously on our synthetic efforts around fragment A and discovered that this region of the molecule was amenable to a structure-activity relationship study that resulted in highly active antiproliferative agents when evaluated in the CEM leukemia cell line. The synthetic analogues were designed to help improve the efficacy and aqueous solubility of the parent compound; therefore, many in this series contained ionizable functional groups such as an amino group, a hydroxy group, or a carboxylic acid. Although several of these analogues showed improvements in potency over cryptophycin 52 in drug-sensitive tumor xenograft models, many lost their activity against Adriamycin-resistant tumor lines. It was discovered on additional in vitro evaluation that these analogues became good substrates of the multidrug resistance transporter P-glycoprotein.
Secretory phospholipase A2 as a tumor-specific trigger for targeted delivery of a novel class of liposomal prodrug anticancer etherlipids
Authors: Jensen Simon S. , Andresen Thomas L. , Davidsen Jesper , Høyrup Pernille , Shnyder Steven D. , Bibby Michael C. , Gill Jason H. , Jørgensen Kent 
Published: June 2022

Abstract
The use of many common clinically relevant chemotherapeutics is often limited due to insufficient delivery to the tumor and dose-limiting systemic toxicities. Therefore, therapeutics that specifically target tumor cells and are nontoxic to normal cells are required. Here, we report the development of a novel class of liposomes composed of lipid prodrugs, which use the increased secretory phospholipase A2 type IIA (sPLA2) activity of the tumor microenvironment as a trigger for the release of anticancer etherlipids (AEL). Treatment of sPLA2-secreting tumor cells in vitro with liposomes consisting of proAELs resulted in growth inhibition comparable with addition of the AELs alone. Using a specific sPLA2 inhibitor, we showed the low cytotoxicity of the nonhydrolyzed proAEL liposomes and have proven the sPLA2 dependency of the activation of proAELs to cytotoxic AELs. In addition, we showed that our proAEL liposomes circumvent the inherent hemolytic toxicities associated with the use of etherlipids, thereby allowing i.v. administration of such therapeutics as nontoxic prodrug liposomes. Furthermore, using a sPLA2-secreting human colon cancer xenograft model, we showed that the proAEL liposomes are capable of inducing a tumor growth delay in vivo. Taken together, these data support the validity of this novel tumor-selective liposomal prodrug delivery strategy. This new approach also provides a promising system for tumor-selective delivery and release of conventional chemotherapeutics encapsulated in the sPLA2-degradable prodrug liposomes.
(−)-Gossypol acts directly on the mitochondria to overcome Bcl-2- and Bcl-XL-mediated apoptosis resistance
Authors: Oliver Christopher L. , Miranda Michelle B. , Shangary Sanjeev , Land Stephanie , Wang Shaomeng , Johnson Daniel E. 
Published: June 2022

Abstract
Aberrant overexpression of antiapoptotic members of the Bcl-2 protein family, including Bcl-2 and Bcl-XL, contributes to malignant transformation and subsequent resistance to traditional chemotherapeutics. Thus, these proteins represent attractive targets for novel anticancer agents. The small molecule, gossypol, was initially investigated as a contraceptive agent, but subsequently has been shown to possess anticancer properties in vitro and in vivo. Recently gossypol has been found to bind to Bcl-XL and, with less affinity, to Bcl-2. Here we investigate the ability of the (−) enantiomer of gossypol, (−)-gossypol, to overcome the apoptosis resistance conferred by Bcl-2 or Bcl-XL overexpression in Jurkat T leukemia cells. (−)-Gossypol potently induced cell death in Jurkat cells overexpressing Bcl-2 (IC50, 18.1 ± 2.6 μmol/L) or Bcl-XL (IC50, 22.9 ± 3.7 μmol/L). Vector-transfected control cells were also potently killed by (−)-gossypol (IC50, 7.0 ± 2.7 μmol/L). By contrast, the chemotherapy drug etoposide only induced efficient killing of vector-transfected cells (IC50, 9.6 ± 2.3μmol/L). Additionally, (−)-gossypol was more efficient than etoposide at inducing caspase-3 activation and phosphatidylserine externalization in the setting of Bcl-2 or Bcl-XL overexpression. (−)-Gossypol-induced apoptosis was associated with Bak activation and release of cytochrome c from mitochondria, suggesting a mitochondrial-mediated apoptotic mechanism. Moreover, (−)-gossypol treatment of isolated mitochondria purified from Bcl-2-overexpressing cells also resulted in cytochrome c release, indicating a possible direct action on Bcl-2 present in the mitochondrial outer membrane. Taken together, these results suggest that (−)-gossypol is a potent and novel therapeutic able to overcome apoptosis resistance by specifically targeting the activity of antiapoptotic Bcl-2 family members. (−)-Gossypol may be a promising new agent to treat malignancies that are resistant to conventional therapies.
A new class of peroxisome proliferator-activated receptor γ (PPARγ) agonists that inhibit growth of breast cancer cells: 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes
Authors: Qin Chunhua , Morrow Derek , Stewart Jessica , Spencer Kyle , Porter Weston , Smith Roger , Phillips Timothy , Abdelrahim Maen , Samudio Ismael , Safe Stephen 
Published: June 2022

Abstract
1,1-Bis(3′-indolyl)-1-(p-trifluoromethylphenyl)methane (DIM-C-pPhCF3) and several p-substituted phenyl analogues have been investigated as a new class of peroxisome proliferator-activated receptor γ (PPARγ) agonists. Structure-activity studies in PPARγ-dependent transactivation assays in MCF-7 breast cancer cells show that 5–20 μm concentrations of compounds containing p-trifluoromethyl, t-butyl, cyano, dimethylamino, and phenyl groups were active, whereas p-methyl, hydrogen, methoxy, hydroxyl, or halogen groups were inactive as PPARγ agonists. Induction of PPARγ-dependent transactivation by 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) and DIM-C-pPhCF3 was inhibited in MCF-7 cells cotreated with the PPARγ-specific antagonist N-(4′-aminopyridyl)-2-chloro-5-nitrobenzamide. In mammalian two-hybrid assays, DIM-C-pPhCF3 and PGJ2 (5–20 μm) induced interactions of PPARγ with steroid receptor coactivator (SRC) 1, SRC2 (TIFII), and thyroid hormone receptor-associated protein 220 but not with SRC3 (AIB1). In contrast, DIM-C-pPhCF3, but not PGJ2, induced interactions of PPARγ with PPARγ coactivator-1. C-substituted diindolylmethanes inhibit carcinogen-induced rat mammary tumor growth, induce differentiation in 3T3-L1 preadipocytes, inhibit MCF-7 cell growth and G0/G1-S phase progression, induce apoptosis, and down-regulate cyclin D1 protein and estrogen receptor α in breast cancer cells. These compounds are a novel class of synthetic PPARγ agonists that induce responses in MCF-7 cells similar to those observed for PGJ2.
Acyclic retinoid activates retinoic acid receptor β and induces transcriptional activation of p21CIP1 in HepG2 human hepatoma cells
Authors: Suzui Masumi , Shimizu Masahito , Masuda Muneyuki , Lim Jin T. E. , Yoshimi Naoki , Weinstein I. Bernard 
Published: June 2022

Abstract
Acyclic retinoid (ACR), a novel synthetic retinoid, has recently been demonstrated by us to inhibit the in vitro growth of human hepatoma cells, and this effect was associated with decreased expression of cell cycle-related molecules. These results, taken together with previous in vitro and clinical studies with ACR, suggest that this agent may be useful in the chemoprevention and therapy of hepatoma and possibly other human malignancies. In the present study, we further examined the molecular effects of ACR on the HepG2 human hepatoma cell line, focusing on the expression of nuclear retinoid receptors and the cell cycle inhibitor protein p21CIP1. Reverse transcription-PCR assays and Western blot analyses indicated that these cells express retinoic acid receptors (RARs) α, β, and γ, retinoid X receptors (RXRs) α and β, and peroxisome proliferator-activated receptors (PPAR) γ mRNA. Treatment with ACR caused a rapid induction within 3 h of RARβ mRNA and the related protein, but there was no significant change in the levels of the mRNA or proteins for RARs α and γ, RXRs α and β, and PPARγ. There was also a rapid increase in p21CIP1 mRNA and protein in HepG2 cells treated with ACR, and this induction occurred via a p53-independent mechanism. In transient transfection reporter assays, we cotransfected the retinoic acid response element-chloramphenicol acetyltransferase (CAT) reporter gene into HepG2 cells together with a RARβ expression vector. RARβ expression markedly stimulated CAT activity (up to about 4-fold) after the addition of ACR. However, CAT activity in the presence of ACR was only about 2-fold higher than that in the absence of ACR, when cells were cotransfected with RARs α and γ or RXRα. These findings suggest that the growth inhibitory effects of ACR are mediated at least in part through RARβ and that both RARβ and p21CIP1 play critical roles in the molecular mechanisms of growth inhibition induced by ACR.
In vitroevaluation of dimethane sulfonate analogues with potential alkylating activity and selective renal cell carcinoma cytotoxicity
Authors: Mertins Susan D. , Myers Timothy G. , Holbeck Susan L. , Medina-Perez Wilma , Wang Elaine , Kohlhagen Glenda , Pommier Yves , Bates Susan E. 
Published: June 2022

AbstractWe identified five structurally related dimethane sulfonates with putative selective cytotoxicity in renal cancer cell lines. These compounds have a hydrophobic moiety linked to a predicted alkylating group. A COMPARE analysis with the National Cancer Institute Anticancer Drug Screen standard agent database found significant correlations between the IC50 of the test compounds and the IC50 of alkylating agents (e.g., r = 0.68, P &lt; 0.00001 for chlorambucil). In this report, we examined whether these compounds had activities similar to those of conventional alkylating agents. In cytotoxicity studies, chlorambucil-resistant Walker rat carcinoma cells were 4- to 11-fold cross-resistant to the test compounds compared with 14-fold resistant to chlorambucil. To determine effects on cell cycle progression, renal cell carcinoma (RCC) line 109 was labeled with bromodeoxyuridine prior to drug treatment. Complete cell cycle arrest occurred in cells treated with an IC90 dose of NSC 268965. p53 protein levels increased as much as 5.7-fold in RCC line 109 and as much as 20.4-fold in breast cancer line MCF-7 following an 18-hour drug exposure. Finally, DNA-protein cross-links were found following a 6-hour pretreatment with all compounds. Thus, the dimethane sulfonate analogues have properties expected of some alkylating agents but, unlike conventional alkylating agents, appear to possess activity against RCC.
Solution of load frequency control through jaya technique with unified power flow controller and redox flow battery
Authors: Panwar Avinash , Agarwal Vinesh , Sharma Gulshan , Akindeji Kayode Timothy , Krishnan Narayanan 
Published: June 2022

This paper proposes the initial <span>strategy of designing two degree of freedom proportional integral derivative (2DOF-PID) made load frequency control (LFC) action optimized using Jaya optimization algorithm for a hydro-hydro system. At first, the PID optimized through Jaya is used for hydro-dominated system, and the comparative analysis of all possible error definitions are carried out to show the benefits of selecting integral time absolute error (ITAE) for LFC. Then, 2DOF-PID is designed for the hydro governing system, and its performance is compared with other designs to show the efficacy of the present LFC about computed error values gain of the various models via graphical LFC. The results obtained through simulations are promising but oscillatory with greater settling time. Hence, the proposed controller is retuned by considering the unified power flow control (UPFC) in arrangement with the tie-line and redox flow battery (RFB) units in area-2, and it is further seen that the outcomes of the application show the prevalence of the proposed work.</span>
Design of a compact and miniature band-pass filter for global positioning system applications
Authors: Kadiri Amal , Tajmouati Abdelali , Zbitou Jamal , Zahraoui Issam , Latrach Mohamed 
Published: June 2022

In this paper, <span>a novel compact band pass filter (BPF) is proposed for global positioning system (GPS) applications. The proposed filter which is based on a microstrip resonator is mounted on a low cost RO4000 substrate with a dielectric constant εr=3.5, a thickness h=1.542 mm, a loss tangent tan (δ)=0.0027. It has a bandwidth from 1.55 GHz to 1.72 GHz. This filter is optimized and validated by using two electromagnetic solvers. The area occupied by this BPF is 33.6×41.24 mm<sup>2</sup>. The final circuit is a low cost BPF and can be associated with passive and active circuits due to the miniature dimensions.</span>