bluuebunny/crossref_metadata_2025_split huggingface dataset:
RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors
Authors: Roulston Anne , Zimmermann Michal , Papp Robert , Skeldon Alexander , Pellerin Charles , Dumas-Bérube Émilie , Dumais Valerie , Dorich Stéphane , Fader Lee D. , Fournier Sara , Li Li , Leclaire Marie-Eve , Yin Shou Yun , Chefson Amandine , Alam Hunain , Yang William , Fugère-Desjardins Chloe , Vignini-Hammond Sabrina , Skorey Kathryn , Mulani Amina , Rimkunas Victoria , Veloso Artur , Hamel Martine , Stocco Rino , Mamane Yael , Li Zuomei , Young Jordan T.F. , Zinda Michael , Black W. Cameron 
Published: December 2021

AbstractAtaxia telangiectasia and Rad3-related (ATR) kinase protects genome integrity during DNA replication. RP-3500 is a novel, orally bioavailable clinical-stage ATR kinase inhibitor (NCT04497116). RP-3500 is highly potent with IC50 values of 1.0 and 0.33 nmol/L in biochemical and cell-based assays, respectively. RP-3500 is highly selective for ATR with 30-fold selectivity over mammalian target of rapamycin (mTOR) and more than 2,000-fold selectivity over ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and phosphatidylinositol 3-kinase alpha (PI3Kα) kinases. In vivo, RP-3500 treatment results in potent single-agent efficacy and/or tumor regression in multiple xenograft models at minimum effective doses (MED) of 5 to 7 mg/kg once daily. Pharmacodynamic assessments validate target engagement, with dose-proportional tumor inhibition of phosphorylated checkpoint kinase 1 (pCHK1) (IC80 = 18.6 nmol/L) and induction of phosphorylated H2A.X variant histone (γH2AX), phosphorylated DNA-PK catalytic subunit (pDNA-PKcs), and phosphorylated KRAB-associated protein 1 (pKAP1). RP-3500 exposure at MED indicates that circulating free plasma levels above the in vivo tumor IC80 for 10 to 12 hours are sufficient for efficacy on a continuous schedule. However, short-duration intermittent (weekly 3 days on/4 days off) dosing schedules as monotherapy or given concomitantly with reduced doses of olaparib or niraparib, maximize tumor growth inhibition while minimizing the impact on red blood cell depletion, emphasizing the reversible nature of erythroid toxicity with RP-3500 and demonstrating superior efficacy compared with sequential treatment. These results provide a strong preclinical rationale to support ongoing clinical investigation of the novel ATR inhibitor, RP-3500, on an intermittent schedule as a monotherapy and in combination with PARP inhibitors as a potential means of maximizing clinical benefit.
NKG7 Is a T-cell–Intrinsic Therapeutic Target for Improving Antitumor Cytotoxicity and Cancer Immunotherapy
Authors: Wen Ti , Barham Whitney , Li Ying , Zhang Henan , Gicobi Joanina K. , Hirdler Jacob B. , Liu Xin , Ham Hyoungjun , Peterson Martinez Kodi E. , Lucien Fabrice , Lavoie Roxane R. , Li Hu , Correia Cristina , Monie Dileep D. , An Zesheng , Harrington Susan M. , Wu Xiaosheng , Guo Ruifeng , Dronca Roxana S. , Mansfield Aaron S. , Yan Yiyi , Markovic Svetomir N. , Park Sean S. , Sun Jie , Qin Hong , Liu Minetta C. , Vasmatzis George , Billadeau Daniel D. , Dong Haidong 
Published: December 2021

Abstract
Cytotoxic CD8+ T cells (CTL) are a crucial component of the immune system notable for their ability to eliminate rapidly proliferating malignant cells. However, the T-cell intrinsic factors required for human CTLs to accomplish highly efficient antitumor cytotoxicity are not well defined. By evaluating human CD8+ T cells from responders versus nonresponders to treatment with immune checkpoint inhibitors, we sought to identify key factors associated with effective CTL function. Single-cell RNA-sequencing analysis of peripheral CD8+ T cells from patients treated with anti–PD-1 therapy showed that cells from nonresponders exhibited decreased expression of the cytolytic granule-associated molecule natural killer cell granule protein-7 (NKG7). Functional assays revealed that reduced NKG7 expression altered cytolytic granule number, trafficking, and calcium release, resulting in decreased CD8+ T-cell–mediated killing of tumor cells. Transfection of T cells with NKG7 mRNA was sufficient to improve the tumor-cell killing ability of human T cells isolated from nonresponders and increase their response to anti–PD-1 or anti–PD-L1 therapy in vitro. NKG7 mRNA therapy also improved the antitumor activity of murine tumor antigen–specific CD8+ T cells in an in vivo model of adoptive cell therapy. Finally, we showed that the transcription factor ETS1 played a role in regulating NKG7 expression. Together, our results identify NKG7 as a necessary component for the cytotoxic function of CD8+ T cells and establish NKG7 as a T-cell–intrinsic therapeutic target for enhancing cancer immunotherapy.
See related article by Li et al., p. 154.
Pulling the Strings of the Tumor Microenvironment
Authors: Burrello Claudia , de Visser Karin E. 
Published: December 2021

Abstract
Macrophages are in the spotlight of cancer immunotherapy research because they exert a wide spectrum of protumorigenic functions. In this issue, Pfirschke and colleagues report that macrophage targeting pulls the strings of the tumor microenvironment, ultimately leading to a coordinated antitumorigenic immune reaction in a lung carcinoma mouse model.
See related article by Pfirschke et al., p. 40. (4).
Property, Custom, and Religion in Early Nineteenth-Century
Bombay
Authors: Issar Sukriti 
Published: December 2021

Abstract
Analysis of a novel source of data about early nineteenth-century Bombay, with a novel methodology, makes an important contribution to debates about inter-religious contact in South Asia. Bombay’s register of sales deeds, which lists the names of buyers, sellers, and neighbors, also permits identification of their religious affiliations when supplemented with archival information about the bureaucratic practices affecting property transactions. Findings suggest that property transactions within religious groups comprised most of the sales (60 percent). Contemporary petitions show that residents sometimes appealed to the state to prevent the sale of property to people who did not share their religion.
‘We are in a Battle with the Virus’: Hamas, Hezbollah, and covid-19
Authors: Alijla Abdalhadi 
Published: December 2021

Abstract
This article examines the response of two non-state actors, Hezbollah and Hamas, to the coronavirus pandemic in Lebanon and Palestine. It studies the patterns of governance, practicalities, leadership, and legitimacy both parties deployed during the Covid-19 crisis. It argues that non-state actors usually imitate states by trying to acquire legitimacy in such cases. The coronavirus was sectarianised, politicised, and used to gain external and local legitimacy by Hamas and Hezbollah, respectively. The success of non-state actors in managing the coronavirus pandemic was rooted in two factors: the existence of a pre-existing and well-developed welfare system, and the party’s capacity to mobilise its constituencies mainly through charismatic leadership. The paper is based on primary sources, including interviews, news articles, and social media.
Academic Integrity and Audiobooks
Authors: Bacaller Sarah 
Published: December 2021

Abstract
Audiobooks offer increased accessibility and new ways of engaging with scholarly texts. Although the development of academic audiobooks is in a relatively early stage, one significant issue that is yet to receive appropriate attention is the presentation of referenced materials in audio form. Presently, this is approached on a case-by-case basis with no centralized industry standards, and so protocols are either set by individual publishers or negotiated between rights-holders and narrators. Narrators usually adopt one of four options for dealing with notes or other referencing tools: complete omission; addition of audio effects to differentiate the reading of references from the primary narrative; reading the reference notes at the end of a chapter or the book; or including with the audiobook files an optional PDF download with reference details. These options give consideration to aesthetic issues, but it is uncertain whether they do justice to questions of academic integrity. The purpose of this article is to encourage scholarly dialogue and a conversation between the audio publishing industry and academia on this issue, and to begin working towards a ‘best practice’ framework that satisfies questions of both aesthetic experience and academic integrity.
So, Did We Really Find Yesayan?
Authors: Aktokmakyan Maral 
Published: December 2021

Abstract
This think piece aims to locate the problematic interest in the work of Zabel Yesayan in the heart of the much broader question of the fate of Armenian literary studies and criticism. The critique presented here provides a quick glance over the timeline of this interest through the intellectual touchstones accomplished over the last two decades then followed by the contemplation of a series of issues that lie behind a particular kind of fetishizing attitude. These issues include the predominant and privileged status of the discipline of history, the misleading state of Yesayan translations, and the illiterate – both in the literal and figurative senses of the word – therefore scandalous state of contemporary academia. My conclusory remarks, returning to what I describe as “Yesayan fever,” are part of an attempt towards a rhizomatic reading that would liberate the author from overloaded feminist and genocide-based readings.
Stratospheric Gravity Waves Excited by a Propagating Rossby Wave Train—A DEEPWAVE Case Study
Authors: Dörnbrack Andreas , Eckermann Stephen D. , Williams Bifford P. , Haggerty Julie 
Published: December 2021

Abstract
Stratospheric gravity waves observed during the DEEPWAVE research flight RF25 over the Southern Ocean are analyzed and compared with numerical weather prediction (NWP) model results. The quantitative agreement of the NWP model output and the tropospheric and lower-stratospheric observations is remarkable. The high-resolution NWP models are even able to reproduce qualitatively the observed upper-stratospheric gravity waves detected by an airborne Rayleigh lidar. The usage of high-resolution ERA5 data—partially capturing the long internal gravity waves—enabled a thorough interpretation of the particular event. Here, the observed and modeled gravity waves are excited by the stratospheric flow past a deep tropopause depression belonging to an eastward-propagating Rossby wave train. In the reference frame of the propagating Rossby wave, vertically propagating hydrostatic gravity waves appear stationary; in reality, of course, they are transient and propagate horizontally at the phase speed of the Rossby wave. The subsequent refraction of these transient gravity waves into the polar night jet explains their observed and modeled patchy stratospheric occurrence near 60°S. The combination of both unique airborne observations and high-resolution NWP output provides evidence for the one case investigated in this paper. As the excitation of such gravity waves persists during the quasi-linear propagation phase of the Rossby wave’s life cycle, a hypothesis is formulated that parts of the stratospheric gravity wave belt over the Southern Ocean might be generated by such Rossby wave trains propagating along the midlatitude waveguide.
Trends of Healthcare-associated Infections in a Tuinisian University Hospital and Impact of COVID-19 Pandemic
Authors: Ghali Hela , Ben Cheikh Asma , Bhiri Sana , Khefacha Selwa , Latiri Houyem Said , Ben Rejeb Mohamed 
Published: December 2021

Background Although efforts to manage coronavirus disease 2019 (COVID-19) pandemic have understandably taken immediate priority, the impacts on traditional healthcare-associated infection (HAI) surveillance and prevention efforts remain concerning. Aim To describe trends in HAIs in a Tunisian university hospital through repeated point prevalence surveys over 9 years, assess the impact of measures implemented for COVID-19 pandemic, and to identify associated factors of HAI. Methods The current study focused on data collected from annual point prevalence surveys conducted from 2012 to 2020. All types of HAIs as defined by the Centers for Disease Control and Prevention (CDC) were included. Data collection was carried out using NosoTun plug. Univariate and multivariate logistic analysis were used to identify HAI risk factors. Results Overall, 2729 patients were observed in the 9 surveys; the mean age was 48.3 ± 23.3 years and 57.5% were male. We identified 267 infected patients (9.8%) and 296 HAIs (10.8%). Pneumonia/lower respiratory tract infections were the most frequent HAI (24%), followed by urinary tract infection (20.9%).The prevalence of infected patients increased from 10.6% in 2012 to 14.9% in 2020. However, this increase was not statistically significant. The prevalence of HAIs increased significantly from 12.3% to 15.5% ( P =.003). The only decrease involved is bloodstream infections (from 2% to 1%). Independent risk factors significantly associated with HAI were undergoing surgical intervention (aOR = 1.7), the use of antibiotic treatment in previous 6 months (aOR = 1.8), peripheral line (aOR=2), parenteral nutrition (aOR=2.4), urinary tract within 7 days (aOR=2.4), central line (aOR = 6.3), and prosthesis (aOR = 12.8), length of stay (aOR = 3), and the year of the survey. Young age was found as protective factor (aOR = .98). Conclusion Contrary to what was expected, we noticed an increase in the HAIs rates despite the preventive measures put in place to control the COVID-19 pandemic. This was partly explained by the vulnerability of hospitalized patients during this period.
Evaluation of Therapeutic Effects of Quercetin Against Achilles Tendinopathy in Rats via Oxidative Stress, Inflammation, Apoptosis, Autophagy, and Metalloproteinases
Authors: Semis Halil Sezgin , Gur Cihan , Ileriturk Mustafa , Kandemir Fatih Mehmet , Kaynar Ozgur 
Published: December 2021

Background: Achilles tendinopathy, seen in athletes and manual labor workers, is an inflammatory condition characterized by chronic tendon pain. Owing to the toxicity that develops in various organs attributed to the use of anti–inflammatory drugs, there is a need for new therapeutic agents. Purpose: In the present study, the effects of quercetin (Que), the one that attracted the most attention of researchers studying this group of flavonoids, were investigated against collagenase–induced tendinopathy. Study Design: Controlled laboratory study. Methods: A total of 35 Sprague-Dawley rats were used in the study. Tendinopathy was created by injecting a single dose of collagenase (10 μL; 10 mg/mL) into the tendons of rats. Thirty minutes after the injection, Que was administered at doses of 25 or 50 mg/kg. Que administration was carried out for 7 days. Animals underwent a motility test at the end of the study. In addition, markers of oxidative stress, inflammation, apoptosis, and autophagy, as well as the expression levels of matrix metalloproteinases (MMPs 2, 3, 9, and 13), ICAM-1, and STAT3, were measured in tendon tissues with biochemical, molecular, and Western blot techniques. Results: The results showed that oxidative stress, inflammation, apoptosis, and autophagy were triggered by the injection of collagenase. In addition, MMPs, ICAM-1, and STAT3 were activated to participate in the development of tendinopathy. Que was found to reduce ICAM-1 levels in tendon tissue. Moreover, Que showed antioxidant, anti–inflammatory, antiapoptotic, and antiautophagic effects on tendons against tendinopathy. More important, Que suppressed the expression of MMPs in the tendon tissues. Conclusion: Que has protective properties against collagenase–induced tendon damage in rats. Clinical Relevance: We believe that with further study, Que may be shown to be an alternative treatment option for athletes or others who experience tendon injuries.
The Effect of Transcultural Nursing Course on Students’ Moral Sensitivity: A Quasi-Experimental Study
Authors: Yüksel Kaçan Cevriye 
Published: December 2021

Introduction: The moral sensitivity of nurses positively affects the quality of patient care. For this reason, nursing students are expected to gain moral sensitivity skills during their education. The aim of the study is to examine the impact of transcultural nursing course (TNC) on the moral sensitivity levels of students. Methods: This study had a quasi-experimental design. The sample consisted of 100 nursing students (intervention: 36 and control: 64). The intervention group was composed of students who had enrolled in the TNC. The data were collected through the Sociodemographic Information Form and the Moral Sensitivity Questionnaire. Independent samples t-test and analysis of variance were used in data analysis. Results: The moral sensitivity levels of the students who received the TNC were significantly higher than those who did not. Discussion: The TNC is an effective teaching method in increasing the moral sensitivity levels of nursing students.
Anatomically Fixed Posterior Malleolar Fractures in Syndesmosis Injuries without Transsyndesmotic Screw Fixation
Authors: Çağlar Ceyhun , Akçaalan Serhat , Akkaya Mustafa 
Published: December 2021

Background: The stability of the syndesmosis is extremely important in terms of syndesmosis injury, ankle instability, and posttraumatic osteoarthritis development following ankle fractures. The aim of this study is to evaluate 1-year radiographic outcomes after posterior malleolar fixation in lateral and posterior malleolar fractures and trimalleolar fractures without transsyndesmotic screw fixation. Methods: Ninety-four patients who underwent posterior malleolar fixation with posterolateral approach between January 2017 and June 2019 were evaluated retrospectively. The patients were evaluated with parameters such as demographic characteristics, fracture type, injury mechanism, physical examination, and radiographic measurements. The stability of the syndesmosis was evaluated by an intraoperative Cotton test and by measuring the tibiofibular overlap, tibiofibular clear space, and medial clear space parameters preoperatively on the immediate postoperative, first-year weightbearing ankle anteroposterior radiographs. Results: In immediate postoperative measurements on radiographs, although the mean tibiofibular overlap ( P < .001) increased, the mean tibiofibular clear space ( P < .001) and mean medial clear space ( P < .001) decreased compared with preoperative radiographs. Immediate postoperative mean tibiofibular overlap, tibiofibular clear space, and medial clear space compared with postoperative first-year mean tibiofibular overlap ( P = .39), tibiofibular clear space ( P = .23), and medial clear space ( P = .43) were not statistically significant. Bone union was completed radiographically at a median of 3.4 ± 1.8 months after surgery. Conclusion: After posterior malleolar fractures, anatomic reduction of the posterior malleolus and posterior inferior tibiofibular ligament complex provides strong syndesmosis stability as measured radiographically at 1 year. Patients may not need additional transsyndesmotic screw fixation. Level of Evidence: Level IV, case series.
Fabrication of carbon fibers from the cupric ion impregnated and thermally stabilized poly(hexamethylene adipamide) precursor
Authors: Erzurumluoglu Levent , Rahman Md. Mahbubor , Demirel Tuba , Karacan Ismail 
Published: December 2021

The conversion of poly (hexamethylene adipamide) or polyamide 66 precursor fiber to carbon fibers was accomplished through thermal stabilization and carbonization processes. Thermal stabilization was conducted of cupric chloride (CuCl2)–ethanol-impregnated polyamide 66 (PA66) fibers in the air. To determine the influence of heating rate on the fiber structure and properties of the resultant carbon fibers, carbonization experiments were performed at selected temperatures of 500, 700, 900, and 1100°C using 2.5 and 5 °C/min heating rates with no dwelling. The results conclusively revealed that the volume density and tensile properties of the PA66 fiber were higher at 2.5 °C/min heating rate. After fixing the heating rate as 2.5°C/min, further carbonization experiments were conducted at temperatures from 500 to 1100°C, using increments of 100°C with no dwelling time. Linear density, volume density, fiber diameter, carbon yield, elemental composition, tensile, and electrical properties exhibited a strong dependence on the carbonization temperature. After taking into account the effects of structural defects (i.e., microvoids), tensile strength, and tensile modulus of the carbon fibers increased to 794 MPa and 92.4 GPa, respectively, when carbonized at 1100°C. X-ray diffraction analysis of the carbon fibers further revealed the existence of a greatly disordered (i.e., amorphous) structure, which developed during the carbonization process. FT-IR analysis confirmed the formation of highly aromatic carbon clusters at temperatures of 500°C and higher. The outcomes of electrical conductivity in this study confirm that the PA66 precursor was converted into a semi-conducting state once it was carbonized.
Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders
Authors: Whittaker Elizabeth , Dadabayev Alisher R. , Joshi Sonalee A. , Glue Paul 
Published: December 2021

Background: Anxiety disorders are common, associated with significant burden of disease, and have high levels of treatment resistance. Low-dose ketamine has been extensively studied in treatment-resistant depression, with fewer reports in treatment-resistant anxiety disorders. Aims: This systematic review and meta-analysis collected efficacy, safety, and tolerability data for ketamine as a treatment for anxiety spectrum disorders. Methods: We conducted a systematic search for randomized controlled trials (RCTs) of acute ketamine treatment for patients with anxiety disorders. Open-label trials of ketamine maintenance therapy were also considered. Qualitative and, where possible, quantitative syntheses of findings were performed using Review Manager software (RevMan). Acute dose-response and maintenance treatment data were also collected. Results: There were six eligible acute RCTs – two in social anxiety disorder (SAD), three in post-traumatic stress disorder (PTSD), and one in obsessive-compulsive disorder (OCD). Four of the six showed significant improvement in anxiety rating scores in ketamine compared with control groups. Pooled analysis showed ketamine was associated with an increased likelihood of treatment response for SAD (odds ratio (OR): 28.94; 95% confidence interval [CI]: 3.45–242.57; p = 0.002) but not for PTSD (OR: 2.03; 95% CI: 0.67–6.15; p = 0.21). A dose-response profile was observed for ketamine and changes in SAD symptoms, with doses ⩾0.5 mg/kg associated with greater reduction in anxiety rating scores than lower doses. Ketamine maintenance therapy was associated with sustained anxiolytic effects and improved social and/or work functioning. Conclusion: These preliminary analyses suggest that acute ketamine may be broadly effective across treatment-resistant anxiety spectrum disorders. These effects can be prolonged with maintenance treatment. Future studies will be needed to provide critical knowledge gaps around off-label use, side effects, and potential risks for abuse in clinical settings.