bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer
Authors: Puyang Xiaoling , Furman Craig , Zheng Guo Zhu , Wu Zhenhua J. , Banka Deepti , Aithal Kiran , Agoulnik Sergei , Bolduc David M. , Buonamici Silvia , Caleb Benjamin , Das Subhasree , Eckley Sean , Fekkes Peter , Hao Ming-Hong , Hart Andrew , Houtman René , Irwin Sean , Joshi Jaya J. , Karr Craig , Kim Amy , Kumar Namita , Kumar Pavan , Kuznetsov Galina , Lai Weidong G. , Larsen Nicholas , Mackenzie Crystal , Martin Lesley-Ann , Melchers Diana , Moriarty Alyssa , Nguyen Tuong-Vi , Norris John , O'Shea Morgan , Pancholi Sunil , Prajapati Sudeep , Rajagopalan Sujatha , Reynolds Dominic J. , Rimkunas Victoria , Rioux Nathalie , Ribas Ricardo , Siu Amy , Sivakumar Sasirekha , Subramanian Vanitha , Thomas Michael , Vaillancourt Frédéric H. , Wang John , Wardell Suzanne , Wick Michael J. , Yao Shihua , Yu Lihua , Warmuth Markus , Smith Peter G. , Zhu Ping , Korpal Manav 
Published: July 2018

Abstract
Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERαWT and ERαMUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERαWT and ERαY537S breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERαWT and ERαMUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs.
Significance: Nearly 30% of endocrine therapy–resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERαWT and ERαMUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176–93. ©2018 AACR.
This article is highlighted in the In This Issue feature, p. 1047
Safety and Efficacy of Re-treating with Immunotherapy after Immune-Related Adverse Events in Patients with NSCLC
Authors: Santini Fernando C. , Rizvi Hira , Plodkowski Andrew J. , Ni Andy , Lacouture Mario E. , Gambarin-Gelwan Maya , Wilkins Olivia , Panora Elizabeth , Halpenny Darragh F. , Long Niamh M. , Kris Mark G. , Rudin Charles M. , Chaft Jamie E. , Hellmann Matthew D. 
Published: July 2018

Abstract
Considering retreatment following recovery from an immune-related adverse event (irAE) is a common clinical scenario, but the safety and benefit of retreatment is unknown. We identified patients with advanced non–small cell lung cancer (NSCLC) treated with anti-PD-(L)1 who had treatment held due to irAEs and divided them into two groups: those retreated with anti-PD-(L)1 (retreatment cohort) or those who had treatment stopped (discontinuation cohort). Out of 482 NSCLC patients treated with anti-PD-(L)1, 68 (14%) developed a serious irAE requiring treatment interruption. Of these, 38 (56%) were retreated and 30 (44%) had treatment discontinued. In the retreatment cohort, 18 (48%) patients had no subsequent irAEs, 10 (26%) had recurrence of the initial irAE, and 10 (26%) had a new irAE. Most recurrent/new irAEs were mild (58% grade 1–2) and manageable (84% resolved or improved to grade 1). Two treatment-related deaths occurred. Recurrent/new irAEs were more likely if the initial irAE required hospitalization, but the initial grade and time to retreatment did not influence risk. Among those with no observed partial responses prior to the irAE, progression-free survival (PFS) and overall survival (OS) were longer in the retreatment cohort. Conversely, for those with objective responses prior to the irAE, PFS and OS were similar in the retreatment and discontinuation cohorts. Among patients with early objective responses prior to a serious irAE, outcomes were similar, whether or not they were retreated. Together, data suggest that benefit may occur with retreatment in patients with irAEs who had no treatment response prior to irAE onset. Cancer Immunol Res; 6(9); 1093–9. ©2018 AACR.
In Hyperacute Recanalization Therapy, Early Hospital Arrival Improves Outcome in Patients with Large Artery Occlusion
Authors: Aoki Junya , Suzuki Kentaro , Suda Satoshi , Okubo Seiji , Mishina Masahiro , Nishiyama Yasuhiro , Sakamoto Yuki , Kimura Kazumi 
Published: July 2018

<b><i>Background:</i></b> It is unknown whether the effect of onset-­­to-door (OTD) time on clinical outcomes differs between ­patients with and without large artery occlusion (LAO) who undergo hyperacute recanalization therapy. <b><i>Methods:</i></b> Hyperacute recanalization therapy includes intravenous thrombolysis tissue-plasminogen activator (tPA), and endovascular therapy (EVT). Favorable clinical outcome was defined as modified Rankin Scale of ≤2 at discharge. <b><i>Results:</i></b> Among 164 patients, 117 (71%) patients received tPA, 86 (52%) received EVT, and 39 (24%) received tPA and EVT. One hundred and fifteen patients (70%) were classified into the LAO group and 49 (30%) into the non-LAO group. In the total cohort, multivariate regression analysis showed OTD time (OR 0.809 [95% CI 0.693–0.944], <i>p</i> = 0.007) was an independent factor related to the favorable outcome. Similarly, among patients with LAO, OTD was an independent negative factor for the favorable outcome (0.779 [0.646–0.940], <i>p</i> = 0.009). On the contrary, OTD was not associated with the favorable outcome (1.5 [0.7–2.5] vs. 1.7 [1.1–3.2], <i>p</i> = 0.155) in patients without LAO. This was confirmed with multivariate regression analysis, which did not show OTD to be an independent factor for the favorable outcome (0.900 [0.656–1.236], <i>p</i> = 0.516). <b><i>Conclusion</i></b>: The effect of early hospital arrival on clinical outcome differed between patients with and without LAO.
Association of Autonomic Nervous System Abnormalities on Head-Up Tilt Table Test with Joint Hypermobility
Authors: Adamec Ivan , Junakovic Anamari , Krbot Skorić Magdalena , Habek Mario 
Published: July 2018

<b><i>Aim:</i></b> The aim of this study was to investigate the association of autonomic nervous system abnormalities on head-up tilt table test (HUTT) with generalized joint hypermobility, expressed by Beighton score (BS). <b><i>Methods:</i></b> This was a prospective study that included 115 consecutive patients (91 females; mean age 34.35 ± 14.11) referred either for the HUTT or testing of the cardiovascular autonomic reflexes together with HUTT. Generalized joint hypermobility was evaluated according to the BS system after which HUTT was performed. Clinically significant BS was considered if ≥4. <b><i>Results:</i></b> Fifteen patients (15.1%) had BS ≥4. Results of the HUTT were normal in 58 (50.4%) patients and in 57 (49.6%) patient HUTT was abnormal. Fifteen (13.0%) patients fulfilled criteria for orthostatic hypotension, 30 (26.1%) for reflex syncope and 21 (18.3%) for postural orthostatic tachycardia syndrome. Patients with pathological findings on HUTT had significantly higher BS compared to patients with normal HUTT (median 1 vs. 0, <i>p</i> = 0.001). There was a significant association between participants with BS ≥4 and pathological HUTT (χ[1] = 6.392, <i>p</i> = 0.011). Results of the multivariate regression analysis revealed that increase in the BS is associated with the increased likelihood of HUTT pathology (Exp[B] 1.44, 95% CI 1.084–1.922, <i>p</i> = 0.012), while increase in age is associated with lower risk of HUTT pathology (Exp[B] 0.968, 95% CI 0.939–0.998, <i>p</i> = 0.036). <b><i>Conclusion:</i></b> There is an association between autonomic nervous system abnormalities on HUTT test and generalized joint hypermobility.
Effect of Sucroferric Oxyhydroxide on Fibroblast Growth Factor 23 Levels in Hemodialysis Patients
Authors: Otsuki Tomoyasu , Utsunomiya Kei , Moriuchi Masari , Horikoshi Shu , Okamura Masahiro , Suzuki Hiroko , Okamura Makiyo , Maruyama Noriaki , Shibahara Nami , Abe Masanori 
Published: July 2018

<b><i>Objective:</i></b> This study investigated the effects of sucroferric oxyhydroxide on fibroblast growth factor (FGF)-23 and dose reduction of erythropoiesis-stimulating agents (ESA) and intravenous saccharated ferric oxide in hemodialysis patients. <b><i>Methods:</i></b> In this prospective, open-label, parallel-group, multicenter trial involving patients receiving lanthanum carbonate hydrate, eligible patients were randomized to a sucroferric oxyhydroxide group or a control group. Hemoglobin, serum phosphate, FGF-23, iron, and ferritin levels, as well as transferrin saturation, doses of intravenous saccharated ferric oxide and ESA administered, and the erythropoietin responsiveness index (ERI) were monitored for 24 weeks. <b><i>Results:</i></b> Sixty-eight eligible patients were allocated to receive sucroferric oxyhydroxide (<i>n</i> = 34) or serve as controls (<i>n</i> = 34). Data for 31 patients in the sucroferric oxyhydroxide group and 32 in the control group were analyzed. Serum phosphate was equally well controlled in both groups. In the sucroferric oxyhydroxide group, intact FGF-23 levels decreased significantly from baseline at the end of the study (<i>p </i>= 0.01) and there was a significant difference compared with the control group (<i>p</i> = 0.035). Required doses of ESA and ERI were significantly reduced in the sucroferric oxyhydroxide group decreased significantly. The dose of intravenous saccharated ferric oxide required in the sucroferric oxyhydroxide group was significantly lower than that at baseline (<i>p</i> = 0.006) and in the control group (<i>p</i> = 0.003). <b><i>Conclusions:</i></b> Treatment of hyperphosphatemia with sucroferric oxyhydroxide was effective in patients on hemodialysis, resulting in decreased serum FGF-23 levels and a reduction in the required dose of saccharated ferric oxide.
Novel Hemoglobin-Based Oxygen Carrier Bound With Albumin Shows Neuroprotection With Possible Antioxidant Effects
Authors: Gekka Masayuki , Abumiya Takeo , Komatsu Teruyuki , Funaki Ryosuke , Kurisu Kota , Shimbo Daisuke , Kawabori Masato , Osanai Toshiya , Nakayama Naoki , Kazumata Ken , Houkin Kiyohiro 
Published: July 2018

Background and Purpose—
A hemoglobin-albumin cluster, 1 core of hemoglobin covalently bound with 3 shell albumins, designated as HemoAct was developed as a hemoglobin-based oxygen carrier. We aim to investigate neuroprotection by HemoAct in transient cerebral ischemia and elucidate its underlying mechanisms.

Methods—
Male rats were subjected to 2-hour transient middle cerebral artery occlusion and were then administered HemoAct transarterially at the onset of reperfusion. Neurological and pathological findings were examined after 24 hours of reperfusion to identify neuroprotection by HemoAct. Intermittent measurements of cortical blood flow and oxygen content were performed, and a histopathologic analysis was conducted on rats during the early phase of reperfusion to assess the therapeutic mechanism of HemoAct. In addition, the antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells.

Results—
Neurological deterioration, infarct and edema development, and the activation of MMP-9 (matrix metalloprotease-9) and lipid peroxidation after 24 hours of reperfusion were significantly ameliorated by the HemoAct treatment. Reductions in blood flow and tissue partial oxygen pressure in the cortical penumbra after 6 hours of reperfusion were significantly ameliorated by the HemoAct treatment. The histopathologic analysis of the cortical penumbra revealed that HemoAct in HemoAct-treated rats showed superior microvascular perfusion with the mitigation of microvascular narrowing changes than autologous erythrocytes in nontreated rats. Although HemoAct extravasated into the ischemic core with serum protein, it did not induce an increase in serum extravasation or reactive oxygen species production in the ischemic core. In vitro experiments with rat brain microvascular endothelial cells revealed that HemoAct significantly suppressed cellular reactive oxygen species production in hypoxia/reoxygenation-treated cells, similar to albumin.

Conclusions—
HemoAct exerted robust neuroprotection in transient cerebral ischemia. Superior microvascular perfusion with an oxygen delivery capability and possible antioxidant effects appear to be the underlying neuroprotective mechanisms.
Inhibition of PAI (Plasminogen Activator Inhibitor)-1 Improves Brain Collateral Perfusion and Injury After Acute Ischemic Stroke in Aged Hypertensive Rats
Authors: Chan Siu-Lung , Bishop Nicole , Li Zhaojin , Cipolla Marilyn J. 
Published: July 2018

Background and Purpose—
Aging and hypertension, comorbidities prevalent in the stroke population, are associated with poor collateral status and worsened stroke outcome. However, underlying mechanisms by which these conditions affect stroke outcome are not clear. We studied the role of PAI (plasminogen activator inhibitor)-1 that is increased in aging and hypertension on brain and vascular expression of inflammatory factors and perfusion that may contribute to worse stroke outcomes.

Methods—
Aged (≈50 weeks) and young (≈18 weeks) spontaneously hypertensive rats (SHR) were subjected to ischemia by middle cerebral artery occlusion (2 hours) and reperfusion (2 hours) with or without treatment with the PAI-1 inhibitor TM5441. Changes in middle cerebral artery and collateral perfusion territories were measured by multisite laser Doppler. Reactivity to TM5441 was studied using isolated and pressurized leptomeningeal anastomotic arterioles. Brain injury was determined by 2,3,5-triphenyltetrazolium staining and quantitative immunohistochemistry of amyloid-β-42, PAI-1, and hemoglobin. Circulating inflammatory factors were measured by ELISA.

Results—

Changes in cerebral blood flow during middle cerebral artery occlusion were similar between groups, with both having poor collateral perfusion and incomplete reperfusion. However, aged SHR had greater brain injury versus young (41±2 versus 23±2%,
P
<0.05) as well as increased brain deposition of amyloid-β-42 and circulating oxLDL (oxidized low-density lipoprotein). Erythrocyte aggregation and hemorrhage within the injured brain was observed in 50% of aged but no young SHR, with increased circulating PAI-1 in this subgroup of aged SHR (16±3 versus 6±2 ng/mL,
P
<0.05). PAI-1 inhibition with TM5441 improved brain injury but did not affect hemorrhage. TM5441 increased collateral perfusion by 38±7% and dilated leptomeningeal anastomotic arterioles by 44±10%, which was abolished by nitric oxide synthase inhibition.

Conclusions—
Increased injury in aged SHR seemed to be related to poor collateral perfusion, hemorrhagic transformation, increased amyloid-β-42, and oxidative stress. PAI-1 inhibition reduced infarction in both groups of SHR that possibly due, in part, to increased collateral perfusion.
Intracranial Hemorrhage in Deep Vein Thrombosis/Pulmonary Embolus Patients Without Atrial Fibrillation
Authors: Lamsam Layton , Sussman Eric S. , Iyer Aditya K. , Bhambhvani Hriday P. , Han Summer S. , Skirboll Stephen , Ratliff John K. 
Published: July 2018

Background and Purpose—
Deep vein thrombosis (DVTs) is a common disease with high morbidity if it progresses to pulmonary embolus (PE). Anticoagulation is the treatment of choice; warfarin has long been the standard of care. Early experience with direct oral anticoagulants (DOACs) suggests that these agents may be may be a safer and equally effective alternative in the treatment of DVT/PE. Nontraumatic intracranial hemorrhage (ICH) is one of the most devastating potential complications of anticoagulation therapy. We sought to compare the rates of ICH in patients treated with DOACs versus those treated with warfarin for DVT/PE.

Methods—
The MarketScan Commercial Claims and Medicare Supplemental databases were used. Adult DVT/PE patients without known atrial fibrillation and with prescriptions for either a DOAC or warfarin were followed for the occurrence of inpatient admission for ICH. Coarsened exact matching was used to balance the treatment cohorts. Cox proportional-hazards regressions and Kaplan-Meier survival curves were used to estimate the association between DOACs and the risk of ICH compared with warfarin.

Results—

The combined cohort of 218 620 patients had a median follow-up of 3.0 months, mean age of 55.4 years, and was 52.1% women. The DOAC cohort had 26 980 patients and 8 ICH events (1.0 cases per 1000 person-years), and the warfarin cohort had 191 640 patients and 324 ICH events (3.3 cases per 1000 person-years;
P
<0.0001). The DOAC cohort had a lower hazard ratio for ICH compared with warfarin in both the unmatched (hazard ratio=0.26;
P
=0.0002) and matched (hazard ratio=0.20;
P
=0.0001) Cox proportional-hazards regressions.

Conclusions—
DOACs show superior safety to warfarin in terms of risk of ICH in patients with DVT/PE.
Acoustic niche partitioning in five Cuban frogs of the genus Eleutherodactylus
Authors: Bignotte-Giró Irelis , Fong G. Ansel , López-Iborra Germán M. 
Published: July 2018

Abstract
Acoustic segregation is a way to reduce competition and allows for species coexistence within anuran communities. Thus, separation in at least one acoustic niche dimension is expected, which also contributes to achieving effective communication among frogs. Here we studied an assemblage of five terrestrial egg-laying anuran species, all in the genus Eleutherodactylus, in a montane rainforest in eastern Cuba. Our aim was to determine if partitioning exists between these species in any dimension (time, signal frequency or space) of the acoustic niche. The studied assemblage had the following characteristics: (1) there was one diurnal species, two species with calling activity throughout the day and two species that call at night; (2) only two species overlapped in call frequencies and most had different calls, both in terms of dominant frequencies and in temporal characteristics; and (3) males of the species that overlapped in vocalizing time or signal frequency used different calling microhabitats or heights. This study provides evidence for the acoustic niche hypothesis in anurans, showing low probabilities of interference in sound communication among these frogs. The five species were separated in at least one of the three acoustic dimensions (calling time, frequency and site) as it occurs in mainland communities with more sympatric species of several genera. Conversely, species in single-genus communities studied in Puerto Rico overlapped completely in calling times. This seems to be due to the higher number of sympatric species at our site.
Immunocompetence and parasite infestation in a melanistic and normally-coloured population of the lacertid lizard, Podarcis siculus
Authors: Baeckens Simon , Van Damme Raoul 
Published: July 2018

Abstract
Melanism is the occurrence of individuals that are darker in skin pigmentation than their conspecifics, which is a common colour polymorphism among vertebrates. Due to the pleotropic effects of the POMC gene that is responsible for melanin-based colouration, dark pigmentation often co-varies with a range of other phenotypic traits. Still, not much is known on the link between melanin-based colouration and immunity in lizards. In this study, we examined and compared the immunocompetence and degree of ectoparasite infestation of Podarcis siculus lizards from a fully melanistic population on an islet in the Tyrrhenian Sea, with conspecifics from a ‘normally’-coloured population on the mainland. Our findings show that both males and females from the melanistic population were less parasitized by ectoparasites and had a greater cellular immune response to a phytohemagglutinin injection than normally-coloured conspecifics. This outcome is in line with the “genetic link hypothesis”, which predicts that melanistic individuals will be more resistant to parasites than non-melanistic individuals due to the pleiotropic POMC gene. In addition, we found correlative evidence for a link between ectoparasite load and PHA immune response, but this was only true for males from the normally-coloured population. Immunological data on additional melanistic and non-melanistic populations of Podarcis siculus in the Mediterranean basin would provide us better insight into patterns of co-variation between immunity and melanism in lizards.
Contemporary and Traditional Voices: Reactions to Same-Sex Marriage Legislation in the Evangelical Lutheran Church of Finland and the Orthodox Church of Finland
Authors: Metso Pekka , Kallatsa Laura 
Published: July 2018

Abstract
This article studies the debate on same-sex marriage in the early 21st century, within the two national churches of Finland, the Evangelical Lutheran Church and the Orthodox Church. Legislation facilitating the so-called “gender-neutral marriage” came into effect in Finland in March 2017. In their official teachings, both churches emphasize marriage as a union between a man and a woman. An awareness of the rights of sexual minorities has, however, increased in both churches, and has given rise to the debate on how same-sex marriage should be perceived. While holding on to the traditional view of marriage, both churches have sought ways to recognize and affirm the position of sexual minorities. This has caused tension within the churches. As the majority church, the Lutheran church in particular faces strong pressure to accept same-sex weddings in the church. For the advocates of sexual minorities within the Orthodox Church, recognition of sexual minorities seems to be the main objective, rather than promoting same-sex weddings.
Experiences of (Mis)recognition of Same-Sex Partnerships in the Evangelical Lutheran Church of Finland
Authors: Hellqvist Elina , Vähäkangas Auli 
Published: July 2018

Abstract
The article discusses the recognition of same-sex partnerships in the Evangelical Lutheran Church of Finland (ELCF). The main focus is on the experiences of recognition and misrecognition of same-sex couples when the couples have asked for a prayer on behalf of their registered partnership. The findings of this study confirm that the researched experiences of recognition have two dimensions, vertical and horizontal. Vertical recognition deals with institutional recognition and experiences with the sacred. Horizontal recognition entails experiences of interpersonal recognition. Narrated experiences often contained both horizontal and vertical dimensions of (mis)recognition. Recognition is a social phenomenon. Participants of the study had two distinct social contexts for recognition. One is the more loosely defined “rainbow community”, the other the formally authoritative, institutional ELCF. Most of the interviewees had positive experiences of recognition from the informal community but mainly negative experiences of misrecognition from the institutional ELCF. The difficult balancing between the conviction of the equal human dignity of each individual and the understanding of marriage as a social category for heterosexuals only led to same-sex couples’ experience of not being treated as equal members of the church. The study affirmed the importance of experiences and feelings as indicators in identifying a valid struggle for recognition.