bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of novel furo[2,3‐d]pyrimidin‐2‐one–1,3,4‐oxadiazole hybrid derivatives as dual antiviral and anticancer agents that induce apoptosis
Authors: El Mansouri Az‐eddine , Oubella Ali , Dânoun Karim , Ahmad Mehdi , Neyts Johan , Jochmans Dirk , Snoeck Robert , Andrei Graciela , Morjani Hamid , Zahouily Mohamed , Lazrek Hassan B. 
Published: June 2021

AbstractA new series of furo[2,3‐d]pyrimidine–1,3,4‐oxadiazole hybrid derivatives were synthesized via an environmentally friendly, multistep synthetic tool and a one‐pot Songoashira‐heterocyclization protocol using, for the first time, nanostructured palladium pyrophosphate (Na2PdP2O7) as a heterogeneous catalyst. Compounds 9a–c exhibited broad‐spectrum activity with low micromolar EC50 values toward wild and mutant varicella‐zoster virus (VZV) strains. Compound 9b was up to threefold more potent than the reference drug acyclovir against thymidine kinase‐deficient VZV strains. Importantly, derivative 9b was not cytostatic at the maximum tested concentration (CC50 > 100 µM) and had an acceptable selectivity index value of up to 7.8. Moreover, all synthesized 1,3,4‐oxadiazole hybrids were evaluated for their cytotoxic activity in four human cancer cell lines: fibrosarcoma (HT‐1080), breast (MCF‐7 and MDA‐MB‐231), and lung carcinoma (A549). Data showed that compound 8f exhibits moderate cytotoxicity, with IC50 values ranging from 13.89 to 19.43 µM. Besides, compound 8f induced apoptosis through caspase 3/7 activation, cell death independently of the mitochondrial pathway, and cell cycle arrest in the S phase for HT1080 cells and the G1/M phase for A549 cells. Finally, the molecular docking study confirmed that the anticancer activity of the synthesized compounds is mediated by the activation of caspase 3.
Parent responsiveness mediates the association between hyporeactivity at age 1 year and communication at age 2 years in children at elevated likelihood of ASD
Authors: Grzadzinski Rebecca , Nowell Sallie W. , Crais Elizabeth R. , Baranek Grace T. , Turner‐Brown Lauren , Watson Linda R. 
Published: June 2021

AbstractStudies suggest that higher parent responsiveness is associated with higher child language abilities. Infants and toddlers later diagnosed with autism spectrum disorder (ASD) often display hyporeactivity to sensory stimuli, which has also been associated with lower child communication abilities and lower parent responsiveness. Yet, whether parent responsiveness mediates the relationship between child hyporeactivity and later communication outcomes remains unexplored. This study is a secondary data analysis which includes children (n = 83; 56 males) identified as at elevated likelihood of later ASD. Children completed an observational measure of sensory reactivity and a standard developmental assessment at 14 (Time 1) and 23 months old (Time 2). At each time point, parents reported on the child's adaptive communication behaviors and sensory behaviors, and Parent Verbal Responsiveness (AvgPVR) was coded from parent–child free‐play videos. Results indicated that the association between child sensory hyporeactivity at Time 1 (observed and parent‐reported) and communication at Time 2 (observed and parent reported) was significantly mediated by AvgPVR. Although child hyporeactivity predicts poorer communication outcomes, increased parent verbal responsiveness may attenuate this negative impact. Parent responsiveness, a focus of many parent‐mediated interventions, may be an important mechanism of treatment response that should be directly tested in future research.Lay SummaryToddlers at elevated likelihood of autism spectrum disorder (ASD) are often under‐reactive (hyporeactive) to sensory stimuli. This hyporeactivity slows learning of communication skills and provides parents with fewer opportunities to respond to their children. In this study, children with hyporeactivity at 14 months generally had poorer communication at 23 months; however, the more responsive their parents were, the weaker the relationship between early hyporeactivity and later communication. Thus, increasing parent responsiveness may lead to better communication outcomes for toddlers with the early ASD symptom of hyporeactivity.
Performance of prostate health index and PSA density in a diverse biopsy‐naïve cohort with mpMRI for detecting significant prostate cancer
Authors: Carbunaru Samuel , Stinson James , Babajide Rilwan , Hollowell Courtney M. P. , Yang Ximing , Sekosan Marin , Ferrer Karen , Kajdacsy‐Balla Andre , Abelleira Josephine , Ruden Maria , King‐Lee Patrice , Dalton Daniel P. , Casalino David D. , Kittles Rick A. , Gann Peter H. , Schaeffer Edward M. , Murphy Adam B. 
Published: June 2021

AbstractObjectiveTo compare Prostate Health Index (PHI) and prostate‐specific antigen (PSA) density as secondary tests after multiparametric magnetic resonance imaging (mpMRI) in improving the detection accuracy of Gleason grade group (GG) 2‐5 prostate cancer (PCa) and in decreasing unnecessary biopsies in a multiethnic biopsy‐naïve population.MethodsFrom February 2017 to February 2020, we recruited consecutive biopsy‐naïve men in participating urology clinics for elevated PSA levels. They all had a PHI score, mpMRI, and prostate biopsy. Experienced genitourinary radiologists read all mpMRI studies based on PIRADS version 2.0. Logistic regression models were used to generate receiver operating characteristic curves. Models were tested for effect modification between Race (Black vs White) and both PHI and PSA density, and Race and PIRADS to determine if race impacted their prediction accuracy. Sensitivity, specificity, and predictive values of PHI and PSA density thresholds were calculated by PIRADS scores. The primary outcome was GG2‐5 PCa, that is, Gleason score ≥3 + 4.ResultsThe study included 143 men, of which 65 (45.5%) were self‐reported Black. Median age was 62.0 years and 55 men (38.4%) had GG2‐5 PCa. Overall, 18.1% had PIRADS 1‐2, 32.9% had PIRADS 3, and 49.0% had PIRADS 4‐5. For the binary logistic regressions, the interactions between PIRADS and Race (P = .08), Log (PHI) and Race (P = .17), and Log (PSA density) and Race (P = .42) were not statistically significant. Within PIRADS 3 lesions, a PHI ≥49 prevented unnecessary biopsies in 55% of men and missed no GG2‐5 PCa, yielding a negative predictive value of 100%. There was no reliable PHI or PSA density threshold to avoid PCa biopsies in PIRADS 1‐2 or 4‐5.ConclusionsPHI and PSA density can be used after mpMRI to improve the detection of GG2‐5 PCa in a biopsy‐naïve cohort. PHI may be superior to PSA density in PIRADS 3 lesions by avoiding 55% of unnecessary biopsies. Using both PHI and PSA density in series may further increase specificity and lead to fewer unnecessary biopsies, but further larger studies are warranted to determine the optimal threshold of each biomarker.
Peptide nucleic acids and their role in gene regulation and editing
Authors: Perera J. Dinithi R. , Carufe Kelly E. W. , Glazer Peter M. 
Published: June 2021

AbstractThe unique properties of peptide nucleic acid (PNA) makes it a desirable candidate to be used in therapeutic and biotechnological interventions. It has been broadly utilized for numerous applications, with a major focus in regulation of gene expression, and more recently in gene editing. While the classic PNA design has mainly been employed to date, chemical modifications of the PNA backbone and nucleobases provide an avenue to advance the technology further. This review aims to discuss the recent developments in PNA based gene manipulation techniques and the use of novel chemical modifications to improve the current state of PNA mediated gene targeting.
Systems‐level approaches for understanding and engineering of the oleaginous cell factory Yarrowia lipolytica
Authors: Poorinmohammad Naghmeh , Kerkhoven Eduard J. 
Published: June 2021

AbstractConcerns about climate change and the search for renewable energy sources together with the goal of attaining sustainable product manufacturing have boosted the use of microbial platforms to produce fuels and high‐value chemicals. In this regard, Yarrowia lipolytica has been known as a promising yeast with potentials in diverse array of biotechnological applications such as being a host for different oleochemicals, organic acid, and recombinant protein production. Having a rapidly increasing number of molecular and genetic tools available, Y. lipolytica has been well studied amongst oleaginous yeasts and metabolic engineering has been used to explore its potentials. More recently, with the advancement in systems biotechnology and the implementation of mathematical modeling and high throughput omics data‐driven approaches, in‐depth understanding of cellular mechanisms of cell factories have been made possible resulting in enhanced rational strain design. In case of Y. lipolytica, these systems‐level studies and the related cutting‐edge technologies have recently been initiated which is expected to result in enabling the biotechnology sector to rationally engineer Y. lipolytica‐based cell factories with favorable production metrics. In this regard, here, we highlight the current status of systems metabolic engineering research and assess the potential of this yeast for future cell factory design development.
Using EEG to decode semantics during an artificial language learning task
Authors: Foster Chris , Williams Chad C. , Krigolson Olave E. , Fyshe Alona 
Published: June 2021

AbstractBackgroundAs we learn a new nonnative language (L2), we begin to build a new map of concepts onto orthographic representations. Eventually, L2 can conjure as rich a semantic representation as our native language (L1). However, the neural processes for mapping a new orthographic representation to a familiar meaning are not well understood or characterized.MethodsUsing electroencephalography and an artificial language that maps symbols to English words, we show that it is possible to use machine learning models to detect a newly formed semantic mapping as it is acquired.ResultsThrough a trial‐by‐trial analysis, we show that we can detect when a new semantic mapping is formed. Our results show that, like word meaning representations evoked by a L1, the localization of the newly formed neural representations is highly distributed, but the representation may emerge more slowly after the onset of the symbol. Furthermore, our mapping of word meanings to symbols removes the confound of the semantics to the visual characteristics of the stimulus, a confound that has been difficult to disentangle previously.ConclusionWe have shown that the L1 semantic representation conjured by a newly acquired L2 word can be detected using decoding techniques, and we give the first characterization of the emergence of that mapping. Our work opens up new possibilities for the study of semantic representations during L2 learning.
Corporate commitment to climate change action, carbon risk exposure, and a firm's debt financing policy
Authors: Lemma Tesfaye T. , Lulseged Ayalew , Tavakolifar Mohammad 
Published: June 2021

AbstractMotivated by the rising consensus that corporate engagement in climate change actions holds the key for society's transition into environmentally resilient economy, the study examines whether a firm's commitment to climate change action and its carbon risk exposure shape the firm's debt financing policy. Based on insights drawn from signaling, corporate reputation, and agency theories, we develop models that link corporate commitment to climate change actions and a firm's carbon risk exposure with its debt financing decisions. Using data drawn from S&P 500 companies, for years 2015 to 2019, we find a robust evidence that firms that engage in higher levels of commitment to climate change actions issue a higher proportion of debt with longer terms to maturity, even after controlling for their carbon risk exposure. However, we do not find a robust evidence corroborating an association between firms' carbon risk exposure and their debt financing policy. These findings are consistent with arguments that high‐commitment firms enjoy positive reputation, better credit rating, and reduced agency and information asymmetry costs, allowing them to gain easier access to long‐term debt markets.
Impact of the model of long‐term follow‐up care on adherence to guideline‐recommended surveillance among survivors of adolescent and young adult cancers
Authors: Kagramanov Dalia , Sutradhar Rinku , Lau Cindy , Yao Zhan , Pole Jason D. , Baxter Nancy N. , Gupta Sumit , Nathan Paul C. 
Published: June 2021

AbstractPurposeAdolescent and young adult cancer survivors require lifelong healthcare to address the late effects of therapy. We examined the impact of different provider models of long‐term follow‐up (LTFU) care on adherence to recommended surveillance.MethodsWe conducted a retrospective cohort study using administrative health databases in Ontario, Canada. Five‐year survivors were identified from IMPACT, a database of patients aged 15–20.9 years at diagnosis of six cancers between 1992 and 2010. We defined three models of LTFU care hierarchically: specialized survivor clinics (SCCs), general cancer clinics (GCCs), and family physician (FP). We assessed adherence to the Children's Oncology Group surveillance guidelines for cardiomyopathy and breast cancer. Multistate models assessed adherence transitions and impacts of LTFU attendance.ResultsA total of 1574 survivors were followed for a mean of 9.2 years (range 4.3–13.9 years) from index (5‐year survival). The highest level of LTFU attended in the first 2‐years post‐index was a GCC (47%); only 16.7% attended a SCC. By the end of study, 72% no longer attended any of the models of care and only 2% still attended an SCC. Among 188 survivors requiring breast cancer surveillance, 6.9% were adherent to their first required surveillance testing. Attendance at a SCC in the previous year and higher cumulative FP or GCC visits increased the rate of subsequently becoming adherent. Among 857 survivors requiring cardiomyopathy surveillance, 11% were adherent at study entry. Each subsequent SCC visit led to an 11.3% (95% CI: 1.05–1.18) increase in the rate of becoming adherent.ConclusionLTFU attendance and surveillance adherence are sub‐optimal. SCC follow‐up is associated with greater adherence, but few survivors receive such care, and this proportion diminished over time. Interventions are needed to improve LTFU attendance and promote surveillance adherence.
Lifestyle interventions can reduce the risk of Barrett’s esophagus: a systematic review and meta‐analysis of 62 studies involving 250,157 participants
Authors: Zhao Zhanwei , Yin Zifang , Zhang Chaojun 
Published: June 2021

AbstractBackgroundBarrett's esophagus (BE) is a well‐established risk factor for esophageal adenocarcinoma. Our objective was to investigate the effectiveness of lifestyle interventions on BE risk.MethodsWe searched PubMed, Embase, and Web of Science up to 30 September 2020. The summary relative risks (RRs) and 95% confidence intervals (CIs) for the highest versus lowest categories of exposure were assessed. Analyses of subgroup, dose–response, sensitivity, and publication bias were conducted.ResultsSixty‐two studies were included that involved more than 250,157 participants and 22,608 cases. Seven lifestyle factors were investigated: smoking, alcohol, body mass index (BMI), physical activity, sleep time, medication, and diet. We observed statistically significant increased BE risks for smoking (RR = 1.35, 95% CI = 1.16–1.57), alcohol intake (RR = 1.23, 95% CI = 1.13–1.34), body fatness (RR = 1.08, 95% CI = 1.03–1.13), less sleep time (RR = 1.76, 95% CI = 1.24–2.49), and proton pump inhibitors use (RR = 1.64, 95% CI = 1.17–2.29). Reduced risks of BE were found for aspirin (RR = 0.70, 95% CI = 0.58–0.84) and the intake of vitamin C (RR = 0.59, 95% CI = 0.44–0.80), folate (RR = 0.47, 95% CI = 0.31–0.71), and fiber (RR = 0.95, 95% CI = 0.93–0.97). The quality of most included studies was high and the subgroup analysis according to the quality score showed significant results (p < 0.05). There was no publication bias for smoking and alcohol. Although the analysis suggested significant evidence of publication bias for BMI, sensitivity analysis showed that the changes in the recalculated RRs were not significant.ConclusionsThe large meta‐analysis revealed that lifestyle modifications could reduce the risks of BE and, consequently, esophageal adenocarcinoma.
Pediatric oncology clinician communication about sexual health with adolescents and young adults: A report from the children’s oncology group
Authors: Frederick Natasha N. , Bingen Kristin , Bober Sharon L. , Cherven Brooke , Xu Xinxin , Quinn Gwendolyn P. , Ji Lingyun , Freyer David R. 
Published: June 2021

AbstractBackgroundSexual health (SH) is an important concern for adolescents and young adults (AYAs). This study determined current SH communication practices, barriers, and additional resources needed among pediatric oncology clinicians who treat AYAs.MethodsA cross‐sectional survey was developed by the Children's Oncology Group (COG) AYA Committee and sent to pediatric oncologists (n = 1,987; 85.9%) and advanced practice providers (APPs, n = 326; 14.1%) at 226 COG institutions. Responses were tabulated and compared using tests of proportion and trend.ResultsThe sample comprised 602 respondents from 168 institutions and was proportionally representative (468 oncologists [77.7%], 76 APPs [12.6%], 58 unidentified [9.6%]; institutional and provider response rates 74.3% and 26.2%, respectively). Almost half of respondents (41.7%) reported no/small role in SH care. Medical topics were discussed most often, including contraception (67.2%), puberty (43.5%), and sexual activity (37.5%). Topics never/rarely discussed included gender identity (64.5%), sexual orientation (53.7%), and sexual function (50.3%). Frequently cited communication barriers included lack of time, low priority, perceived patient discomfort, and the presence of a parent/guardian. Respondents endorsed the need for further education/resources on sexual function (66.1%), gender identity/sexual orientation (59.5%), and body image (46.6%). Preferred education modalities included dissemination of published guidelines (64.7%), skills training modules (62.9%), and webinars (45.3%). By provider type, responses were similar overall but differed for perception of role, barriers identified, and resources desired.ConclusionsMany pediatric oncology clinicians play minimal roles in SH care of AYAs and most SH topics are rarely discussed. Provider‐directed education/training interventions have potential for improving SH care of AYA cancer patients.
Distinct glycolytic pathway regulation in liver, tumour and skeletal muscle of mice with cancer cachexia
Authors: Visavadiya Nishant P. , Rossiter Harry B. , Khamoui Andy V. 
Published: June 2021

Energetically inefficient inter‐organ substrate shuttles are proposed contributors to cachexia‐related weight loss. Here, we examined glycolytic pathway metabolites, enzyme activity and transport proteins in skeletal muscle, liver and tumours of mice with cachexia‐related weight loss induced by colon‐26 cancer cells. Skeletal muscle of cachexic mice had increased [L‐lactate]/[pyruvate], LDH activity and lactate transporter MCT1. Cachexic livers also showed increased MCT1. This is consistent with the proposal that the rate of muscle‐derived lactate shuttling to liver for use in gluconeogenesis is increased, that is, an increased Cori cycle flux in weight‐losing cachexic mice. A second shuttle between liver and tumour may also contribute to disrupted energy balance and weight loss. We found increased high‐affinity glucose transporter GLUT1 in tumours, suggesting active glucose uptake, tumour MCT1 detection and decreased intratumour [L‐lactate]/[pyruvate], implying increased lactate efflux and/or intratumour lactate oxidation. Last, high [L‐lactate]/[pyruvate] and MCT1 in cachexic muscle provides a potential muscle‐derived lactate supply for the tumour (a ‘reverse Warburg effect’), supporting tumour growth and consequent cachexia. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss. Therapies that aim to normalize dysregulated substrate shuttling among energy‐regulating tissues may alleviate unintended weight loss in cancer cachexia.Significance of the studyCachexia is a serious complication of cancer characterized by severe weight loss, muscle atrophy and frailty. Cachexia occurs in roughly half of all cancer patients, and in up to 80% of patients with advanced disease. Cachexia independently worsens patient prognosis, lowers treatment efficacy, increases hospitalization cost and length of stay, and accounts for 20‐30% of cancer‐related deaths. There are no effective treatments. Our findings suggest several substrate shuttles among liver, skeletal muscle and tumour contribute to metabolic disruption and weight loss in cancer cachexia. Identifying therapies that normalize dysregulated substrate shuttling among energy‐regulating tissues may protect against cachexia‐related weight loss.
Room‐Temperature Phosphorescence Emitters Exhibiting Red to Near‐Infrared Emission Derived from Intermolecular Charge‐Transfer Triplet States of Naphthalenediimide–Halobenzoate Triad Molecules
Authors: Ono Toshikazu , Kimura Kazuki , Ihara Megumi , Yamanaka Yuri , Sasaki Miori , Mori Hirotoshi , Hisaeda Yoshio 
Published: June 2021

AbstractInvited for the cover of this issue is Toshikazu Ono, Yoshio Hisaeda and co‐workers at Kyushu University and their collaborators at Ochanomizu University, Chuo University, and Institute for Molecular Science. The image depicts a molecular assembly structure shining like a jewel, glowing in the red‐to‐near infrared region. Read the full text of the article at 10.1002/chem.202100906.
Kidney outcomes using a sustained ≥40% decline in eGFR: A meta‐analysis of SGLT2 inhibitor trials
Authors: Cherney David Z. I. , Dagogo‐Jack Samuel , McGuire Darren K. , Cosentino Francesco , Pratley Richard , Shih Weichung J. , Frederich Robert , Maldonado Mario , Liu Jie , Wang Shuai , Cannon Christopher P. ,   the VERTIS CV Investigators
Published: June 2021

AbstractBackgroundA recent meta‐analysis of sodium–glucose cotransporter 2 (SGLT2) inhibitor outcome trials reported that SGLT2 inhibitors were associated with reduction in the risk of adverse composite kidney outcomes, with moderate heterogeneity across the trials; however, the endpoints were defined differently across the trials.HypothesisThe apparent heterogeneity of the meta‐analysis of kidney composite outcomes of SGLT2 inhibitor trials will be substantially reduced by using a consistent assessment of sustained ≥40% decline in eGFR/chronic kidney dialysis/transplantation/renal death across trials.MethodsWe performed a meta‐analysis of kidney composite outcomes from the four SGLT2 cardiovascular outcome trial programs conducted in general type 2 diabetes mellitus populations, which included, as a surrogate of progression to kidney failure, a sustained ≥40% decline in eGFR along with kidney replacement therapy and kidney death. The trials assessed were VERTIS CV (NCT01986881), CANVAS Program (NCT01032629 and NCT01989754), DECLARE‐TIMI 58 (NCT01730534), and EMPA‐REG OUTCOME (NCT01131676).ResultsData from the trials comprised 42 516 individual participants; overall, 998 composite kidney events occurred. SGLT2 inhibition was associated with a significant reduction in the kidney composite endpoint (HR 0.58 [95% CI 0.51–0.65]) and with a highly consistent effect across the trials (Q statistic p = .64; I2 = 0.0%).ConclusionsOur meta‐analysis highlights the value of using similarly defined endpoints across trials and supports the finding of consistent protection against kidney disease progression with SGLT2 inhibitors as a class in patients with type 2 diabetes mellitus who either have established atherosclerotic cardiovascular disease or are at high cardiovascular risk with multiple cardiovascular risk factors.