bluuebunny/crossref_metadata_2025_split huggingface dataset:
EGFRAmplification Induces Increased DNA Damage Response and Renders Selective Sensitivity to Talazoparib (PARP Inhibitor) in Glioblastoma
Authors: Wu Shaofang , Gao Feng , Zheng Siyuan , Zhang Chen , Martinez-Ledesma Emmanuel , Ezhilarasan Ravesanker , Ding Jie , Li Xiaolong , Feng Ningping , Multani Asha , Sulman Erik P. , Verhaak Roel G. , de Groot John F. , Heffernan Tim P. , Yung W.K. Alfred , Koul Dimpy 
Published: December 2019

AbstractPurpose:Exploration of novel strategies to extend the benefit of PARP inhibitors beyond BRCA-mutant cancers is of great interest in personalized medicine. Here, we identified EGFR amplification as a potential biomarker to predict sensitivity to PARP inhibition, providing selection for the glioblastoma (GBM) patient population who will benefit from PARP inhibition therapy.Experimental Design:Selective sensitivity to the PARP inhibitor talazoparib was screened and validated in two sets [test set (n = 14) and validation set (n = 13)] of well-characterized patient-derived glioma sphere-forming cells (GSC). FISH was used to detect EGFR copy number. DNA damage response following talazoparib treatment was evaluated by γH2AX and 53BP1 staining and neutral comet assay. PARP–DNA trapping was analyzed by subcellular fractionation. The selective monotherapy of talazoparib was confirmed using in vivo glioma models.Results:EGFR-amplified GSCs showed remarkable sensitivity to talazoparib treatment. EGFR amplification was associated with increased reactive oxygen species (ROS) and subsequent increased basal expression of DNA-repair pathways to counterelevated oxidative stress, and thus rendered vulnerability to PARP inhibition. Following talazoparib treatment, EGFR-amplified GSCs showed enhanced DNA damage and increased PARP–DNA trapping, which augmented the cytotoxicity. EGFR amplification–associated selective sensitivity was further supported by the in vivo experimental results showing that talazoparib significantly suppressed tumor growth in EGFR-amplified subcutaneous models but not in nonamplified models.Conclusions:EGFR-amplified cells are highly sensitive to talazoparib. Our data provide insight into the potential of using EGFR amplification as a selection biomarker for the development of personalized therapy.
The Cytosolic DNA-Sensing cGAS–STING Pathway in Cancer
Authors: Kwon John , Bakhoum Samuel F. 
Published: December 2019

Abstract

The recognition of DNA as an immune-stimulatory molecule is an evolutionarily conserved mechanism to initiate rapid innate immune responses against microbial pathogens. The cGAS–STING pathway was discovered as an important DNA-sensing machinery in innate immunity and viral defense. Recent advances have now expanded the roles of cGAS–STING to cancer. Highly aggressive, unstable tumors have evolved to co-opt this program to drive tumorigenic behaviors. In this review, we discuss the link between the cGAS–STING DNA-sensing pathway and antitumor immunity as well as cancer progression, genomic instability, the tumor microenvironment, and pharmacologic strategies for cancer therapy.

Significance:
The cGAS–STING pathway is an evolutionarily conserved defense mechanism against viral infections. Given its role in activating immune surveillance, it has been assumed that this pathway primarily functions as a tumor suppressor. Yet, mounting evidence now suggests that depending on the context, cGAS–STING signaling can also have tumor and metastasis-promoting functions, and its chronic activation can paradoxically induce an immune-suppressive tumor microenvironment.
CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity
Authors: de Silva Suresh , Fromm George , Shuptrine Casey W. , Johannes Kellsey , Patel Arpita , Yoo Kyung Jin , Huang Kaiwen , Schreiber Taylor H. 
Published: December 2019

AbstractDisrupting the binding of CD47 to SIRPα has emerged as a promising immunotherapeutic strategy for advanced cancers by potentiating antibody-dependent cellular phagocytosis (ADCP) of targeted antibodies. Preclinically, CD47/SIRPα blockade induces antitumor activity by increasing the phagocytosis of tumor cells by macrophages and enhancing the cross-presentation of tumor antigens to CD8+ T cells by dendritic cells; both of these processes are potentiated by CD40 signaling. Here we generated a novel, two-sided fusion protein incorporating the extracellular domains of SIRPα and CD40L, adjoined by a central Fc domain, termed SIRPα-Fc-CD40L. SIRPα-Fc-CD40L bound CD47 and CD40 with high affinity and activated CD40 signaling in the absence of Fc receptor cross-linking. No evidence of hemolysis, hemagglutination, or thrombocytopenia was observed in vitro or in cynomolgus macaques. Murine SIRPα-Fc-CD40L outperformed CD47 blocking and CD40 agonist antibodies in murine CT26 tumor models and synergized with immune checkpoint blockade of PD-1 and CTLA4. SIRPα-Fc-CD40L activated a type I interferon response in macrophages and potentiated the activity of ADCP-competent targeted antibodies both in vitro and in vivo. These data illustrated that whereas CD47/SIRPα inhibition could potentiate tumor cell phagocytosis, CD40-mediated activation of a type I interferon response provided a bridge between macrophage- and T-cell–mediated immunity that significantly enhanced durable tumor control and rejection.
Diagnosis of Acute Kidney Injury in Children Hospitalized in a Sub-Saharan African Unit by Saliva Urea Nitrogen Dipstick Test
Authors: Hussein Rasha H. , Calice-Silva Viviane , Evans Rhys , Levin Nathan W. , Ellidir Rashid A. , Ali Elitigani M. , Bakhiet Yassir , Ahmed Amna , Abdelkareem Asmaa , Abdelraheem Mohamed B. , Kotanko Peter , Pecoits-Filho Roberto , Raimann Jochen G. ,   the International Society of Nephrology (ISN) 0by25 Initiative
Published: December 2019

<b><i>Introduction:</i></b> Acute kidney injury in pediatric patients (pAKI) is common in developing countries and leads to significant morbidity and mortality. Most nephrology services in developing countries are only in larger cities and for that reason many cases remain undiagnosed. We evaluated the performance of a saliva urea nitrogen (SUN) dipstick to diagnose pAKI in Sudan. <b><i>Methods:</i></b> We collected demographic and clinical information, serum creatinine (SCr), blood urea nitrogen (BUN), SUN, and urine output (UO) in children with pAKI. pAKI was diagnosed based on different criteria (Risk, Injury, Failure, Loss of kidney function, and end-stage kidney disease, Acute Kidney Injury Network and Kidney Disease Improving Global Outcomes). We also recorded hospital and 3-months’ mortality and progression to chronic kidney disease (CKD) as outcomes. <b><i>Results:</i></b> We studied 81 patients (mean age 10.7 ± 7 years, 51.9% females) and divided them by age into (a) neonates (&#x3c;120 days; <i>n</i> = 21; 25.9%); (b) ­infants (120–365 days; <i>n</i> = 18; 25.9%); and (c) children (&#x3e;365 days; <i>n</i> = 42; 53.1%). Diagnosis using different pAKI definitions resulted in differences in AKI staging. SUN reliably reflected BUN over the entire study period, regardless of treatment modality or pAKI severity. Neither pAKI staging, SUN, BUN, nor SCr were associated with mortality or progression to CKD. UO predicted all-cause mortality during the 3-months follow-up. <b><i>Conclusion:</i></b> Diagnosis of pAKI using different criteria differs in triage and staging. SUN reflects BUN particularly at higher BUN levels and allows monitoring of treatment responses. Despite the lack of predictive power of SUN to predict hard outcomes, measurement of SUN by dipstick can be used to identify, screen, and monitor pediatric patients with pAKI.
Evidence for a Direct Harmful Effect of Alcohol on Myocardial Health: A Large Cross‐Sectional Study of Consumption Patterns and Cardiovascular Disease Risk Biomarkers From Northwest Russia, 2015 to 2017
Authors: Iakunchykova Olena , Averina Maria , Kudryavtsev Alexander V. , Wilsgaard Tom , Soloviev Andrey , Schirmer Henrik , Cook Sarah , Leon David A. 
Published: December 2019

Background
Alcohol drinking is an increasingly recognized risk factor for cardiovascular disease. However, there are few studies of the impact of harmful and hazardous drinking on biomarkers of myocardial health. We conducted a study in Russia to investigate the impact of heavy drinking on biomarkers of cardiac damage and inflammation.

Methods and Results

The Know Your Heart study recruited a random sample of 2479 participants from the population of northwest Russia (general population) plus 278 patients (narcology clinic subsample) with alcohol problems. The general population sample was categorized into harmful drinkers, hazardous drinkers, nonproblem drinkers, and nondrinkers, according to self‐reported level of alcohol consumption, whereas the narcology clinic sample was treated as the separate group in the analysis. Measurements were made of the following: (1) high‐sensitivity cardiac troponin T, (2) NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), and (3) hsCRP (high‐sensitivity C‐reactive protein). The narcology clinic subsample had the most extreme drinking pattern and the highest levels of all 3 biomarkers relative to nonproblem drinkers in the general population: high‐sensitivity cardiac troponin T was elevated by 10.3% (95%
CI
, 3.7%–17.4%),
NT
‐pro
BNP
by 46.7% (95%
CI
, 26.8%–69.8%), and hsCRP by 69.2% (95%
CI
, 43%–100%). In the general population sample,
NT
‐pro
BNP
was 31.5% (95%
CI
, 3.4%–67.2%) higher among harmful drinkers compared with nonproblem drinkers. Overall,
NT
‐pro
BNP
and hsCRP increased with increasing intensity of alcohol exposure (test of trend
P
<0.001).

Conclusions
These results support the hypothesis that heavy alcohol drinking has an adverse effect on cardiac structure and function that may not be driven by atherosclerosis.
Mean Platelet Volume Does Not Predict Restenosis After Carotid Artery Stenting in Whites
Authors: Haidegger Melanie , Kneihsl Markus , Niederkorn Kurt , Deutschmann Hannes , Augustin Michael , Wünsch Gerit , Fandler-Höfler Simon , Horner Susanna , Fazekas Franz , Enzinger Christian , Gattringer Thomas 
Published: December 2019

Background and Purpose—
Mean platelet volume (MPV) indicates platelet activity possibly affecting patient’s risk for progressive atherosclerotic disease. A recent study identified elevated MPV as a predictor of in-stent restenosis (ISR) after carotid artery stenting (CAS) in a Chinese population. However, the role of MPV on the development of ISR following CAS in whites is yet unknown.

Methods—
We retrospectively identified all consecutive patients who underwent CAS for atherosclerotic disease at our center from 2005 to 2017. All patients were followed clinically and by duplex sonography at 1, 3, and 6 months and annually after CAS. ISR was defined as ≥50% stenosis (NASCET [North American Symptomatic Carotid Endarterectomy Trial] criteria) in the treated vessel. MPV was assessed before CAS, at last follow-up and at the time of ISR detection.

Results—

Of 392 patients with CAS (mean age 68.5±9.5 years, 26.8% women, 42.3% symptomatic stenosis), 54 had ISR after a mean follow-up time of 32 months. Baseline MPV was not different in ISR compared with non-ISR patients (10.7 versus 10.6 fL,
P
=0.316). MPV levels did also not change from baseline to ISR detection (
P
=0.310) and were not associated with recurrent stroke or vascular events (
P
>0.5). Multivariable analysis identified active smoking as the sole risk factor for carotid ISR (odds ratio, 2.53 [95% CI, 1.21–5.29]).

Conclusions—
We did not identify MPV as a risk factor for ISR after CAS in whites. Smoking cessation is an important target to avoid this complication.
Stroke Etiology Modifies the Effect of Endovascular Treatment in Acute Stroke
Authors: Tiedt Steffen , Herzberg Moriz , Küpper Clemens , Feil Katharina , Kellert Lars , Dorn Franziska , Liebig Thomas , Alegiani Anna , Dichgans Martin , Wollenweber Frank A. , Alber B. , Bangard C. , Berrouschot J. , Bode F.J. , Boeckh-Behrens T. , Bohner G. , Bormann A. , Braun M. , Eckert B. , Fiehler J. , Flottmann F. , Gerloff C. , Hamann G.F. , Henn K.H. , Kastrup A. , Kraemer C. , Krause L. , Lehm M. , Liman J. , Lowens S. , Mpotsaris A. , Nolte C.H. , Papanagiotou P. , Petersen M. , Petzold G.C. , Pfeilschifter W. , Psychogios M.N. , Reich A. , von Rennenberg R. , Röther J. , Schäfer J.H. , Siebert E. , Siedow A. , Solymosi L. , Thomalla G. , Thonke S. , Wagner M. , Wunderlich S. , Zweynert S. 
Published: December 2019

Background and Purpose—
Stroke etiology drives thrombus composition. We thus hypothesized that endovascular treatment shows different efficacy in cardioembolic versus noncardioembolic large-vessel occlusions (LVOs).

Methods—
Procedural characteristics, grade of reperfusion, and functional outcome at discharge and 90 days were compared between patients with cardioembolic versus noncardioembolic LVO from the GSR-ET (German Stroke Registry–Endovascular Treatment; n=2589). To determine associations with functional outcome, adjusted odds ratios and 95% CIs were calculated using ordinal multivariable logistic regression models adjusting for potential baseline confounder variables.

Results—

Endovascular treatment of cardioembolic LVO had a higher rate of successful reperfusion (85.6% versus 81.0%;
P
=0.002) and a higher rate of complete reperfusion after a single thrombectomy pass (45.7% versus 38.1%;
P
<0.001) compared with noncardioembolic LVO. Cardioembolic LVO was associated with better functional outcome at discharge (adjusted odds ratio, 1.61 [95% CI, 1.37–1.88]) and 90 days (adjusted odds ratio, 1.29 [95% CI, 1.09–1.53]). In mediation analysis, reperfusion explained 47% of the effect of etiology on functional outcome at discharge.

Conclusions—
These results provide evidence for higher efficacy of endovascular treatment in cardioembolic LVO compared with noncardioembolic LVO.
In Search of a Perfect Match: Jian’an (196-220) Writing about Women and the Formation of a Literati Community
Authors: Hu Qiulei 
Published: December 2019

AbstractThe pursuit of divine women or women with divine beauty is a common theme in the earliest works of Chinese literature. Many fu (rhapsodies) composed at the Western Han courts feature the speaker’s failed pursuit of a beautiful woman. Yet during the Jian’an period, the image of a seductive yet inaccessible woman lost its prominence in the literary imagination and was replaced by a lonely beauty yearning for a worthy match and lamenting the swift passage of time. This transformation had much to do with the social and cultural transitions of this particular historical moment. This article places Jian’an representations of women in the context of group composition and literary communication at the Cao courts, and discusses the literary and political implications of these representations in comparison with previous court writing about women. The article argues that under a new environment of court writing, Jian’an literati transformed the image of beautiful women from the embodiment of imperial power and privilege into the symbol of their ideal personality and shared values. Writing about women became a crucial means to forming a literary and political community, and defining that community’s values and principles in a troubled time.
Living in a tiny world: reproductive biology and population ecology of the Neotropical miniature frog Euparkerella aff. brasiliensis (Terraranae, Strabomantidae)
Authors: Ardenghi Fusinatto Luciana , Diniz Bruno Lamy T. , Soares de Siqueira Andreza , Van Sluys Monique , Sequeira Fernando , Duarte Rocha Carlos F. 
Published: December 2019

Abstract
Miniaturisation is an important evolutionary trend for amphibians and has occurred several times in independent anuran lineages. Most miniaturised frogs live in the leaf litter of tropical forests and have terrestrial reproductive modes. They are expected to have reduced fecundity in number of eggs than larger-bodied related species, but little is known about reproductive cycles and proportion of reproductive females. Lower vagility is also assumed, however, as they are difficult to observe, there is little empirical evidence about their dispersal. We studied the reproductive biology (sex ratio, sexual size dimorphism and fecundity parameters) and population ecology (growth, dispersal, and phenology) of the miniature Guanabara Frog Euparkerella aff. brasiliensis (⩽ 20 mm). We collected and analysed 75 specimens of E. aff. brasiliensis, of which 27 were adult females with vitellogenic oocytes in their ovaries. Fecundity was low for number of eggs (average number = 9.7), but only one adult female had no vitellogenic oocytes. Sex ratio was relatively balanced among sexes, being female-biased (0.92) for all individuals and male-biased (1.17) for adults. Juveniles and ovigerous females were observed throughout the year during the two years of mark-recapture study, which indicates continuous breeding. We captured 121 individuals, of which 12% were recaptured in their original collection sites, suggesting low vagility. We discuss our findings considering the current knowledge about the ecology of miniaturised frogs and other Terraranae and suggest future directions for ecological studies and conservation planning.
Al-Ġazālī e il problema del dissenso religioso (zandaqa)
Authors: Campanini Massimo 
Published: December 2019

Abstract
Al-Ġazālī’s Fayṣal al-tafriqa bayn al-Islām waʾl-zandaqa was aimed to contest religious dissidents, especially Ismaʿili Fāṭimids, but also to promote religious peace in troubled times. It was a fatwā by which al-Ġazālī as a jurist and a muǧaddid planned to achieve a composition between harsh sectarian quarrels. This “mission” did not involve in itself “tolerance” towards opponents, but simply appeasement. Tolerance, however, is more an ethical and juridical than a religious or dogmatic item.
Confronto tra tesi embriologiche: Abū Ḥāmid al-Ġazālī e Abū Bakr al-Rāzī
Authors: Carpentieri Loredana 
Published: December 2019

Abstract
The originality of the embryological thought expressed by Abū Ḥāmid al-Ġazālī (d. 1111) in Iḥyā’ ʿulūm al-dīn (The Revival of the Religious Sciences) is particularly evident if we consider it in the light of the classical medical theories. In this context, it is particularly important to consider the thought of one of the “free thinkers”, against whom al-Ġazālī, ḥujjat al-Islām (the “proof of Islam”), shows his argumentative strength: Abū Bakr al-Rāzī (d. between 925 and 935). The classical Greek theories are an important reference point for Abū Bakr al-Rāzī, as well as for Abū Ḥāmid al-Ġazālī, in spite of their different philosophical approach.
Qualche osservazione in merito al “disinteresse” di Abū Ḥāmid al-Ġazālī (1058-1111) per il “piccolo ǧihād”
Authors: Scarcia Amoretti Biancamaria 
Published: December 2019

Abstract
This paper tries to single out the reasons of al-Ġazālī’s lack of interest in the “lesser ǧihād”, military action. In Iḥyāʾ ʿulūm al-dīn he maintains – according to the Sunna of the Prophet – the superiority of the “greater ǧihād”, the effort upon oneself for moral and religious improvement. By asserting the “golden mean” even on this occasion, he does not consider military action to be condemned, not even after having embraced the mystic path, but he postulates a hierarchy of values based on an esoteric reading of Q 4:95. Al-Ġazālī’s Sufi option is put in context: he writes Iḥyāʾ during the sultanate of Barkyārūq. Though he has “left the world”, he does not cease to consider himself as a muǧaddid and a ‘ālim ḫāṣṣ who should safeguard and promote political and social orthodoxy first and theological orthodoxy later. However, his šafiʿi commitment to this regard allows some exceptions linked to his position as a “courtier” in Iranian area and to the idea of power developed in the Eastern regions. Against al-Māwardī, he claims the ǧihād to be the sultan’s task, not the caliph’s. By refraining from sanctioning the Seljuk military action, al-Ġazālī hopes to preserve, though merely in a symbolical way, the caliph institution, without questioning the fragmentation of the real power. The safety of the umma appears to be secured only until the Eastern regions do not collapse.
Genetic Underpinnings of Musculoskeletal Pain During Treatment With Aromatase Inhibitors for Breast Cancer: A Biological Pathway Analysis
Authors: Zhu Yehui , Koleck Theresa A. , Bender Catherine M. , Conley Yvette P. 
Published: December 2019

Background: Musculoskeletal pain (MSKP) is the most reported symptom during treatment with aromatase inhibitors (AIs) for breast cancer. The mechanisms underlying MSKP are multidimensional and not well understood. The goals of this biological pathway analysis were to (1) gain an understanding of the genetic variation and biological mechanisms underlying MSKP with AI therapy and (2) identify plausible biological pathways and candidate genes for future investigation. Method: Genes associated with MSKP during AI therapy or genes involved in drug metabolism of and response to AIs were identified from the literature. Studies published through February 2019 were queried in PubMed®. The genes identified from the literature were entered into QIAGEN’s Ingenuity® Pathway Analysis (IPA) software to generate canonical pathways, upstream regulators, and networks through a core analysis. Results: The 17 genes identified were ABCB1, ABCG1, CYP17A1, CYP19A1, CYP27B1, CYP2A6, CYP3A4, CYP3A5, ESR1, OATP1B1, OPG, RANKL, SLCO3A1, TCL1A, UGT2A1, UGT2B17, and VDR. These genes are involved in encoding bone-remodeling regulators, drug-metabolizing enzymes (cytochrome P450 family, UDP-glucuronosyltransferases family), or drug transporters (ATP-binding cassette transporters, organic anion transporters). Multiple plausible biological pathways (e.g., nicotine degradation, melatonin degradation) and candidate genes (e.g., NFKB, HSP90, AKT, ERK1/2, FOXA2) are proposed for future investigation based on the IPA results. Conclusion: Multiple genes and molecular-level etiologies may contribute to MSKP with AI therapy in women with breast cancer. Our innovative combination of gene identification from the literature plus biological pathway analysis allowed for the emergence of novel candidate genes and biological pathways for future investigations.
ADAPT technique in ischemic stroke treatment of M2 middle cerebral artery occlusions in comparison to M1 occlusions: Post hoc analysis of the PROMISE study
Authors: Navia Pedro , Schramm Peter , Fiehler Jens 
Published: December 2019

Background/purpose The benefit of endovascular thrombectomy in acute ischemic stroke (AIS) therapy of proximal large vessel occlusions (LVO) is established. However, there are few prospective studies evaluating the use of a direct aspiration first pass technique in distal vessel occlusions. This post hoc analysis of the PROMISE study examines the safety and effectiveness of the Penumbra System with the ACE68 and ACE64 Reperfusion Catheters for aspiration thrombectomy in the M1 and M2 segments of the middle cerebral artery. Methods PROMISE is a prospective, multicenter study that enrolled 204 patients with anterior circulation LVO AIS-treated frontline with ACE68/ACE64 catheters. We compared clinical and angiographic outcomes, complications, and mortality in patients with M1 and M2 occlusions. The association of M1 and M2 location and functional independence or mTICI 2b-3 reperfusion was described in univariable and multivariable analyses. Results One hundred sixty-one patients (124 M1 and 37 M2 locations) met the study criteria. Post procedure mTICI 2b-3 reperfusion (93% vs. 92%, p = 1.00), functional independence (57% vs. 70%, p = 0.18), symptomatic intracranial hemorrhage (1.6% vs. 2.7%, p = 0.55), device- or procedure-related serious adverse events at 30 days (4.0% vs. 8.1%, p = 0.39), and mortality at 90 days (6.6% vs. 2.7%, p = 0.69) were comparable between M1 and M2 occlusions. In multivariable analysis, lower age, lower baseline NIHSS, and shorter time from onset to admission were independent predictors of functional independence. Conclusions For frontline aspiration thrombectomy of stroke, use of large-bore ACE68/ACE64 catheters for treatment of M2 occlusions appeared as safe and effective as for M1 occlusions.