bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eribulin Plus Pembrolizumab in Patients with Metastatic Triple-Negative Breast Cancer (ENHANCE 1): A Phase Ib/II Study
Authors: Tolaney Sara M. , Kalinsky Kevin , Kaklamani Virginia G. , D'Adamo David R. , Aktan Gursel , Tsai Michaela L. , O'Regan Ruth M. , Kaufman Peter A. , Wilks Sharon T. , Andreopoulou Eleni , Patt Debra A. , Yuan Yuan , Wang Grace , Savulsky Claudio , Xing Dongyuan , Kleynerman Ella , Karantza Vassiliki , Diab Sami 
Published: March 2021

Abstract

Purpose:
As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings.

Patients and Methods:
In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1–2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination.

Results:
The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8–38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2–31.1) for stratum 2 (n = 101). Patients with PD-L1–positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1–negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9–54.3) vs 16.1% (95% CI: 5.5–33.7); stratum 2, 24.4% (95% CI: 12.9–39.5) vs 18.2% (95% CI: 8.2–32.7)].

Conclusions:
Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.
A Randomized Phase II Study of Androgen Deprivation Therapy with or without Palbociclib in RB-positive Metastatic Hormone-Sensitive Prostate Cancer
Authors: Palmbos Phillip L. , Daignault-Newton Stephanie , Tomlins Scott A. , Agarwal Neeraj , Twardowski Przemyslaw , Morgans Alicia K. , Kelly Wm. Kevin , Arora Vivek K. , Antonarakis Emmanuel S. , Siddiqui Javed , Jacobson Jon A. , Davenport Matthew S. , Robinson Dan R. , Chinnaiyan Arul M. , Knudsen Karen E. , Hussain Maha 
Published: March 2021

Abstract

Purpose:
Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, blocks proliferation in a RB and cyclin D–dependent manner in preclinical prostate cancer models. We hypothesized that cotargeting androgen receptor and cell cycle with palbociclib would improve outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Patients and Methods:
A total of 60 patients with RB-intact mHSPC were randomized (1:2) to Arm 1: androgen deprivation (AD) or Arm 2: AD + palbociclib. Primary endpoint was PSA response rate (RR) after 28 weeks of therapy. Secondary endpoints included safety, PSA, and clinical progression-free survival (PFS), as well as PSA and radiographic RR. Tumors underwent exome sequencing when available. Circulating tumor cells (CTC) were enumerated at various timepoints.

Results:
A total of 72 patients with mHSPC underwent metastatic disease biopsy and 64 had adequate tissue for RB assessment. A total of 62 of 64 (97%) retained RB expression. A total of 60 patients initiated therapy (Arm 1: 20; Arm 2: 40). Neutropenia was the most common grade 3/4 adverse event in Arm 2. Eighty percent of patients (Arm 1: 16/20, Arm 2: 32/40; P = 0.87) met primary PSA endpoint ≤4 ng/mL at 28 weeks. PSA undetectable rate at 28 weeks was 50% and 43% in Arms 1 and 2, respectively (P = 0.5). Radiographic RR was 89% in both arms. Twelve-month biochemical PFS was 69% and 74% in Arms 1 and 2, respectively (P = 0.72). TP53 and PIK3 pathway mutations, 8q gains, and pretreatment CTCs were associated with reduced PSA PFS.

Conclusions:
Palbociclib did not impact outcome in RB-intact mHSPC. Pretreatment CTC, TP53 and PIK3 pathway mutations, and 8q gain were associated with poor outcome.
Aberrant Claudin-6–Adhesion Signaling Promotes Endometrial Cancer Progression via Estrogen Receptor α
Authors: Kojima Manabu , Sugimoto Kotaro , Kobayashi Makoto , Ichikawa-Tomikawa Naoki , Kashiwagi Korehito , Watanabe Takafumi , Soeda Shu , Fujimori Keiya , Chiba Hideki 
Published: March 2021

Abstract

Cell adhesion proteins not only maintain tissue integrity, but also possess signaling abilities to organize diverse cellular events in a variety of physiologic and pathologic processes; however, the underlying mechanism remains obscure. Among cell adhesion molecules, the claudin (CLDN) family is often aberrantly expressed in various cancers, but the biological relevance and molecular basis for this observation have not yet been established. Here, we show that high CLDN6 expression accelerates cellular proliferation and migration in two distinct human endometrial cancer cell lines in vitro. Using a xenograft model, we also revealed that aberrant CLDN6 expression promotes tumor growth and invasion in endometrial cancer tissues. The second extracellular domain and Y196/200 of CLDN6 were required to recruit and activate Src-family kinases (SFK) and to stimulate malignant phenotypes. Knockout and overexpression of ESR1 in endometrial carcinoma cells showed that the CLDN6-adhesion signal links to estrogen receptor α (ERα) to advance tumor progression. In particular, aberrant CLDN6–ERα signaling contributed to collective cell behaviors in the leading front of endometrial cancer cells. Importantly, we demonstrate that CLDN6/SFK/PI3K-dependent AKT and SGK (serum- and glucocorticoid-regulated kinase) signaling in endometrial cancer cells targets Ser518 in the human ERα to activate ERα transcriptional activity in a ligand-independent manner, thereby promoting tumor progression. Furthermore, CLDN6, at least in part, also regulated gene expression in an ERα-independent manner.

Implications:
The identification of this machinery highlights regulation of the transcription factors by cell adhesion to advance tumor progression.
Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti–PD-1 Therapy Efficacy
Authors: Montfort Anne , Bertrand Florie , Rochotte Julia , Gilhodes Julia , Filleron Thomas , Milhès Jean , Dufau Carine , Imbert Caroline , Riond Joëlle , Tosolini Marie , Clarke Christopher J. , Dufour Florent , Constantinescu Andrei A. , Junior Nilton De França , Garcia Virginie , Record Michel , Cordelier Pierre , Brousset Pierre , Rochaix Philippe , Silvente-Poirot Sandrine , Therville Nicole , Andrieu-Abadie Nathalie , Levade Thierry , Hannun Yusuf A. , Benoist Hervé , Meyer Nicolas , Micheau Olivier , Colacios Céline , Ségui Bruno 
Published: March 2021

Abstract
Dysregulation of lipid metabolism affects the behavior of cancer cells, but how this happens is not completely understood. Neutral sphingomyelinase 2 (nSMase2), encoded by SMPD3, catalyzes the breakdown of sphingomyelin to produce the anti-oncometabolite ceramide. We found that this enzyme was often downregulated in human metastatic melanoma, likely contributing to immune escape. Overexpression of nSMase2 in mouse melanoma reduced tumor growth in syngeneic wild-type but not CD8-deficient mice. In wild-type mice, nSMase2-overexpressing tumors showed accumulation of both ceramide and CD8+ tumor-infiltrating lymphocytes, and this was associated with increased level of transcripts encoding IFNγ and CXCL9. Overexpressing the catalytically inactive nSMase2 failed to alter tumor growth, indicating that the deleterious effect nSMase2 has on melanoma growth depends on its enzymatic activity. In vitro, small extracellular vesicles from melanoma cells overexpressing wild-type nSMase2 augmented the expression of IL12, CXCL9, and CCL19 by bone marrow–derived dendritic cells, suggesting that melanoma nSMase2 triggers T helper 1 (Th1) polarization in the earliest stages of the immune response. Most importantly, overexpression of wild-type nSMase2 increased anti–PD-1 efficacy in murine models of melanoma and breast cancer, and this was associated with an enhanced Th1 response. Therefore, increasing SMPD3 expression in melanoma may serve as an original therapeutic strategy to potentiate Th1 polarization and CD8+ T-cell–dependent immune responses and overcome resistance to anti–PD-1.
O descompasso entre a estrutura acadêmica e a estrutura museal em museus universitários: o caso do Museu Nacional (UFRJ)
Authors: Reis Silvia , Witovisk Luciana , Targino Mariane , Britto Marcelo , Santos Fernanda Pires 
Published: March 2021

O Museu Nacional foi criado em 1818, por D. João VI. Em 200 anos passou pela estruturação de suas coleções, pela incorporação à Universidade do Brasil, em 1946, atual Universidade Federal do Rio de Janeiro, e tornou-se referência nacional e internacional nas áreas da História Natural e Antropologia por meio de suas coleções e excelência em ensino, pesquisa e extensão. O incêndio ocorrido em 2 de setembro de 2018 marcou mais um importante capítulo da sua história – a luta pela reconstrução. Parte desse esforço foi a composição de uma comissão de servidores que se debruçou sobre a revisão e construção de um novo regimento para a instituição. Assim, este trabalho traz à luz análises sobre a complexidade da estrutura do Museu Nacional e debate alguns problemas práticos que dificultam a sua plena realização como museu e parte integrante de uma estrutura universitária. Tal debate é extensível e imprescindível para os museus universitários, onde a estrutura museal pode ser passível de limitações por uma estrutura universitária voltada para unidades acadêmicas padrão ou órgãos suplementares não autônomos, e que não contempla as particularidades do funcionamento de um museu. Por fim, é proposta a criação de uma estrutura museal-acadêmica, onde todas as categorias de servidores públicos poderiam atuar de forma colaborativa, em prol de uma instituição diversa, dinâmica, plural, em diálogo aberto com a universidade e a sociedade, pronta para enfrentar os novos paradigmas do século XXI.
Clinical Profile and Health Disparities in a Multiethnic Cohort of Patients With Hypertrophic Cardiomyopathy
Authors: Butters Alexandra , Semsarian Caitlin R. , Bagnall Richard D. , Yeates Laura , Stafford Fergus , Burns Charlotte , Semsarian Christopher , Ingles Jodie 
Published: March 2021

Background:
Clinical studies of hypertrophic cardiomyopathy are over-represented by individuals of European ethnicity, with less known about other ethnic groups. We investigated differences between patients in a multiethnic Australian hypertrophic cardiomyopathy population.

Methods:
We performed a retrospective cohort study of 836 unrelated hypertrophic cardiomyopathy probands attending a specialized clinic between 2002 and 2020. Major ethnic groups were European (n=611), East Asian (n=75), South Asian (n=58), and Middle Eastern and North African (n=68). The minor ethnicity groups were Oceanian (n=9), People of the Americas (n=7), and African (n=8). One-way ANOVA with Dunnett post hoc test and Bonferroni adjustment were performed.

Results:

Mean age of the major ethnic groups was 54.9±16.9 years, and 527 (65%) were male. Using the European group as the control, East Asian patients had a lower body mass index (29 versus 25 kg/m
2
,
P
<0.0001). South Asians had a lower prevalence of atrial fibrillation (10% versus 31%,
P
=0.024). East Asians were more likely to have apical hypertrophy (23% versus 6%,
P
<0.0001) and Middle Eastern and North African patients more likely to present with left ventricular outflow tract obstruction (46% versus 34%,
P
=0.0003). East Asians were less likely to undergo genetic testing (55% versus 85%,
P
<0.0001) or have an implantable cardioverter-defibrillator implanted (19% versus 36%,
P
=0.037). East Asians were more likely to have a causative variant in a gene other than
MYBPC3
or
MYH7
, whereas Middle Eastern and North African and South Asians had the highest rates of variants of uncertain significance (27% and 21%,
P
<0.0001).

Conclusions:
There are few clinical differences based on ethnicity, but importantly, we identify health disparities relating to access to genetic testing and implantable cardioverter-defibrillator use. Unless addressed, these gaps will likely widen as we move towards precision-medicine–based care of individuals with hypertrophic cardiomyopathy.
Right Ventricular Ejection Fraction for the Prediction of Major Adverse Cardiovascular and Heart Failure-Related Events
Authors: Purmah Yanish , Lei Lucy Y. , Dykstra Steven , Mikami Yoko , Cornhill Aidan , Satriano Alessandro , Flewitt Jacqueline , Rivest Sandra , Sandonato Rosa , Seib Michelle , Lydell Carmen P. , Howarth Andrew G. , Heydari Bobak , Merchant Naeem , Bristow Michael , Fine Nowell , Gaztanaga Juan , White James A. 
Published: March 2021

Background:
There is increasing evidence that right ventricular ejection fraction (RVEF) may provide incremental value to left ventricular (LV) ejection fraction for the prediction of major adverse cardiovascular events. To date, generalizable utility for RVEF quantification in patients with cardiovascular disease has not been established. Using a large prospective clinical outcomes registry, we investigated the prognostic value of RVEF for the prediction of major adverse cardiovascular events- and heart failure-related outcomes.

Methods:
Seven thousand one hundred thirty-one consecutive patients with known or suspected cardiovascular disease undergoing cardiovascular magnetic resonance imaging were prospectively enrolled. Multichamber volumetric quantification was performed by standardized operational procedures. Patients were followed for the primary composite outcome of all-cause death, survived cardiac arrest, admission for heart failure, need for transplantation or LV assist device, acute coronary syndrome, need for revascularization, stroke, or transient ischemic attack. A secondary, heart failure focused outcome of heart failure admission, need for transplantation/LV assist device or death was also studied.

Results:

Mean age was 54±15 years. The mean LV ejection fraction was 55±14% (range 6%–90%) with a mean RVEF of 54±10% (range 9%–87%). At a median follow-up of 908 days, 870 (12%) patients experienced the primary composite outcome and 524 (7%) the secondary outcome. Each 10% drop in RVEF was associated with a 1.3-fold increased risk of the primary outcome (
P
<0.001) and 1.5-fold increased risk of the secondary outcome (
P
<0.001). RVEF was an independent predictor following comprehensive covariate adjustment, inclusive of LV ejection fraction. Patients with an RVEF<40% experienced a 3.1-fold risk of the primary outcome (
P
<0.001) with a 1-year cumulative event rate of 22% versus 7% above this cutoff.

Conclusions:
RVEF is a powerful and independent predictor of major adverse cardiac events with broad generalizability across patients with known or suspected cardiovascular disease. These findings support migration towards biventricular phenotyping for the classification of risk in clinical practice.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04367220.
Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Imaging Predicts Vein Wall Scarring and Statin Benefit in Murine Venous Thrombosis
Authors: Kessinger Chase W. , Qi Guanming , Hassan Malek Z.O. , Henke Peter K. , Tawakol Ahmed , Jaffer Farouc A. 
Published: March 2021

Background:

The postthrombotic syndrome is a common, often morbid sequela of venous thrombosis (VT) that arises from thrombus persistence and inflammatory scarring of juxtaposed vein walls and valves. Noninvasive
18
F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging can measure neutrophil inflammation in VT. Here, we hypothesized (1) early fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) VT inflammation can predict subsequent vein wall scarring (VWS) and (2) statin therapy can reduce FDG-PET VT inflammation and subsequent VWS.

Methods:
C57BL/6J mice (n=75) underwent induction of stasis-induced VT of the inferior vena cava or jugular vein. Inferior vena cava VT mice (n=44) were randomized to daily oral rosuvastatin 5 mg/kg or saline starting at day −1. Subgroups of mice then underwent FDG-PET/CT 2 days after VT induction. On day 14, a subset of mice was euthanized, and VWS was assessed via histology. In vitro studies were further performed on bone marrow-derived neutrophils.

Results:

Statin therapy reduced early day 2 FDG-PET VT inflammation, thrombus neutrophil influx, and plasma IL (interleukin)-6 levels. At day 14, statin therapy reduced VWS but did not affect day 2 thrombus mass, cholesterol, or white blood counts, nor reduce day 2 glucose transporter 1 or myeloperoxidase expression in thrombus or in isolated neutrophils. In survival studies, the day 2 FDG-PET VT inflammation signal as measured by mean and maximum standardized uptake values predicted the extent of day 14 VWS (area under the receiver operating characteristic curve =0.82) with a strong correlation coefficient (
r
) of
r
=0.73 and
r
=0.74, respectively. Mediation analyses revealed that 40% of the statin-induced VWS reduction was mediated by reductions in VT inflammation as quantified by FDG-PET.

Conclusions:
Early noninvasive FDG-PET/CT imaging of VT inflammation predicts the magnitude of subsequent VWS and may provide a new translatable approach to identify individuals at risk for postthrombotic syndrome and to assess anti-inflammatory postthrombotic syndrome therapies, such as statins.
Does the intrusion of an avian nest predator elicit a change in the behaviour of a canopy-nesting passerine?
Authors: Sharp Alexander R. , Islam Kamal 
Published: March 2021

Abstract
Many studies have shown that nest predators affect their prey indirectly by inducing changes in the behaviour of the prey. Studies suggest that the type and degree of nest defence strategies depends heavily on species, along with nest type and location. One such strategy, nest vigilance, allows individuals to collect information and make informed decisions based on their surroundings. In this study, we simulated the intrusion of a common avian nest predator (blue jay, Cyanocitta cristata) into the territory of nesting cerulean warblers (Setophaga cerulea) and evaluated eight different behavioural variables to determine their response to the nest predator. Female cerulean warblers were more vigilant on their nest when exposed to a potential predator compared to a nest with lower threat of predation. Females exposed to a nest predator increased incubation bout by 109% and brooding bout by 60%. Our data also suggest that male cerulean warblers reduce their provisioning rate during the early nestling stage (−1 feeding/hour) and late nestling stage (−3 feedings/hour), although more data are needed. Modification of incubation bout length and nestling provisioning rate are common strategies employed by songbirds to reduce activity around the nest, by decreasing detection opportunities of visually-oriented nest predators. Currently, the only understanding we have on how cerulean warblers respond to a nest predator is based on observational data. The results of this study provide the first evidence that cerulean warblers are able to identify species that pose a threat to the safety of their nest, and that they modify their behaviour to reduce nest detection by predators. The results of this study provide a better understanding of a relatively unknown aspect of the breeding behaviour of this species. This study is also first to describe how an open-cup, canopy-nesting species responds to an increase in nest predation threat.
Does anthropogenic noise promotes advertisement call adjustments in the rubí poison frog Andinobates bombetes?
Authors: Jiménez-Vargas Gina Marcela , Vargas-Salinas Fernando 
Published: March 2021

Abstract
Anthropogenic noise, characterized by higher intensities at low frequencies, can restrict acoustic communication between conspecifics and eventually reduce the fitness of populations. We analysed changes in the call features of 52 males of the poison frog A. bombetes subjected to anthropogenic noise through playback experiments. Thirty-one males did not call during playbacks, but the remaining 21 males did. Fourteen of those 21 males increased their dominant call frequency on average 130.76 Hz when exposed to noise. Males did not increase or diminish the emission rate, number of pulses, and duration of their calls. It is possible that males by increasing the frequency of their calls are showing a behavioural strategy that maintain signal-to-noise ratio, which allows them to communicate acoustically in noisy habitats. Further studies are necessary to corroborate this hypothesis given that the magnitude of the increase in call frequency was small (<100 Hz) for most males.
Trajectories of change in depression symptoms and suicidal ideation over the course of evidence-based treatment for depression: Secondary analysis of a randomised controlled trial of cognitive behavioural therapy plus fluoxetine in young people
Authors: Witt Katrina , Madsen Trine , Berk Michael , Dean Olivia , Chanen Andrew , McGorry Patrick D , Cotton Sue , Davey Christopher G , Hetrick Sarah 
Published: March 2021

Objectives: Effective treatment of depression is a key target for suicide prevention strategies. However, only around one-third of young people with suicide risk respond to evidence-based treatments. Understanding the trajectory of suicidal ideation, as a marker of suicide risk, over the course of evidence-based treatment for depression might provide insight into more targeted and effective treatments. Methods: This is a secondary analysis of data from the multicentre Youth Depression Alleviation–Combined Treatment trial. A total of 153 young people aged 15–25 years diagnosed with major depressive disorder were randomly assigned in this double-blind, placebo-controlled trial to either cognitive behavioural therapy plus fluoxetine or cognitive behavioural therapy plus placebo. Participants were assessed for depression and suicidal ideation at baseline and at weeks 4, 8 and 12. Results: Using group-based trajectory modelling, we identified two distinct depression trajectories. The first (Improving; 54.9%; n = 83) comprised those who experienced a consistent decline in depression symptoms. The second (Persisting; 45.1%; n = 70) comprised those who, despite treatment, still had clinically significant levels of depression by the end of treatment. For suicidal ideation, we identified four distinct trajectories: Non-clinical (15.5%; n = 20), Low Improving (47.1%; n = 75), High Improving (24.8%; n = 38) and High Persisting (12.7%; n = 20). Treatment allocation was not significantly associated with trajectory membership for either depression or suicidal ideation. Conclusion: Understanding the course of depression and suicidal ideation during treatment has important implications for managing suicide risk. The findings suggest that there is an identifiable group of young people for whom enhanced psychological and/or pharmacological intervention might be required to ensure a better treatment response. Specific interventions for those with suicidal ideation may also be prudent from the outset. Clinical trial registration: The Youth Depression Alleviation–Combined Treatment trial was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612001281886).