bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer
Authors: Lee Jin Sun , Yost Susan E. , Blanchard Suzette , Schmolze Daniel , Yin Hongwei Holly , Pillai Raju , Robinson Kim , Tang Aileen , Martinez Norma , Portnow Jana , Wen Wei , Yim John H. , Brauer Heather Ann , Ren Yuqi , Luu Thehang , Mortimer Joanne , Yuan Yuan 
Published: November 2019

Abstract

Background
Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC.

Methods
The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks).

Results
Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0–8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]).

Conclusion
Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle.

Trial registration
ClinicalTrials.gov, NCT02120469. Registered 18 April 2014
Comparative risk of malignancies and infections in patients with rheumatoid arthritis initiating abatacept versus other biologics: a multi-database real-world study
Authors: Simon Teresa A. , Boers Maarten , Hochberg Marc , Baker Nicole , Skovron Mary L. , Ray Nitesh , Singhal Sanket , Suissa Samy , Gomez-Caminero Andres 
Published: November 2019

Abstract

Background
Patients with rheumatoid arthritis (RA) are at an increased risk of developing certain cancers and infections compared with the general population. Biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) are effective treatment options for RA, but limited evidence is available on the comparative risks among b/tsDMARDs. We assessed the risk of malignancies and infections in patients with RA who initiated abatacept versus other b/tsDMARDs in a real-world setting.

Methods
This retrospective, observational study used administrative data from three large US healthcare databases (MarketScan, PharMetrics, and Optum) to identify patients treated with abatacept or other b/tsDMARDs. In both groups, age-stratified incidence rates (IRs) with 95% confidence intervals (CIs) were calculated for total malignancy and hospitalized infections; propensity score matching and Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% CIs for total malignancy, lung cancer, lymphoma, breast cancer, non-melanoma skin cancer (NMSC), hospitalized infections, opportunistic infections, and tuberculosis (TB), both within individual databases and in meta-analyses across the three databases.

Results
A rounded total of 19.2, 13.6, and 4.2 thousand patients initiating abatacept and 55.3, 40.8, and 13.8 thousand initiating other b/tsDMARDs were identified in the MarketScan, PharMetrics, and Optum databases, respectively. The IRs for total malignancy and hospitalized infections were similar between the two groups in each age stratum. In meta-analyses, total malignancy risk (HR [95% CI] 1.09 [1.02–1.16]) of abatacept versus other b/tsDMARDs was slightly but statistically significantly increased; small, but not statistically significant, increases were seen for lung cancer (1.10 [0.62–1.96]), lymphoma (1.27 [0.94–1.72]), breast cancer (1.15 [0.92–1.45]), and NMSC (1.10 [0.93–1.30]). No significant increase in hospitalized infections (0.96 [0.84–1.09]) or opportunistic infections (1.06 [0.96–1.17]) was seen. For TB, low event counts precluded meta-analysis.

Conclusions
In this real-world multi-database study, the risks for specific cancers and infections did not differ significantly between patients in the abatacept and other b/tsDMARDs groups. The slight increase in total malignancy risk associated with abatacept needs further investigation. These results are consistent with the established safety profile of abatacept.
Acute kidney injury associated with febuxostat and allopurinol: a post-marketing study
Authors: Rey Amayelle , Batteux Benjamin , Laville Solène M. , Marienne Justine , Masmoudi Kamel , Gras-Champel Valérie , Liabeuf Sophie 
Published: November 2019

Abstract

Background
For patients with recurrent flares of gout, tophi, urate crystal arthropathy, and renal stones, urate-lowering therapies (ULTs, including allopurinol and febuxostat) are the first-line treatment. Due to the widespread use of these ULTs (especially in patients with impaired renal function), assessment of the associated renal risk is essential. Accordingly, we performed a disproportionality analysis of reported cases of acute renal failure (ARF) associated with allopurinol and febuxostat.

Methods
We carried out a case/non-case study of the World Health Organization’s VigiBase® pharmacovigilance database between January 1, 2008, and December 31, 2018. The frequency of reports of ARF as a standardized Medical Dictionary for Regulatory Activities query for allopurinol and febuxostat was compared with that of all other reports for the two drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]. The results’ stability was assessed in a series of sensitivity analyses (notably after the exclusion of putative competing drugs).

Results
Among 3509 “suspected drug” notifications for febuxostat and 18,730 for allopurinol, we identified respectively 317 and 1008 cases of ARF. Acute renal failure was reported significantly more frequently for febuxostat and allopurinol than for other drugs (ROR [95%CI] 5.67 [5.05–6.36] and 3.25 [3.05–3.47], respectively). For both drugs, the ROR was higher in women than in men, respectively 11.60 [9.74–13.82] vs. 3.14 [2.69–3.67] for febuxostat and 4.45 [4.04–4.91] vs. 2.29 [2.11–2.50] for allopurinol. The sensitivity analyses confirmed the disproportionality for these two ULTs.

Conclusions
Acute renal failure was reported respectively 5.7 and 3.3 times more frequently for febuxostat and for allopurinol than for other drugs. Due to the potential consequences of ARF, physicians should take account of this disproportionality signal when prescribing the ULTs febuxostat and allopurinol.
Lower serum 25-hydroxyvitamin D3 concentration is associated with higher pain and disability in subjects with low back pain: a case–control study
Authors: Pishgahi Alireza , Dolatkhah Neda , Shakouri Seyed Kazem , Hashemian Maryam , Amiri Atefeh , Delkhosh Reihany Morteza , Jahanjou Fatemeh 
Published: November 2019

ObjectivesLow back pain (LBP) is a common medical problem worldwide. The aim of this study is to evaluate the association between serum concentration of 25-hydroxivitamin D3 and functional disability in patients suffering from LBP in a sample of Azeri middle-aged subjects, North West of Iran.ResultsIn this case–control study, 63 eligible patients with LBP and 55 healthy subjects enrolled in the study. Peripheral venous blood was taken for evaluating the serum concentration of 25-hydroxivitamin D3. We recognized factors related with LBP by multiple regression analyses. The average serum 25-hydroxivitamin D3 concentration in case group was significantly lower than that of the matched controlled group (26.25 ± 15.95 vs. 34.20 ± 14.92, p-value < 0.01 respectively). Subjects with vitamin D deficiency or insufficiency were more likely to exhibit LBP than subjects with normal serum 25-hydroxivitamin D3 concentration [(OR = 2.388, 95% CI (1.114 to 5.119)]. According to the partial correlation analysis, there was a reverse correlation between serum 25-hydroxivitamin D3 concentration with functional disability measured by Modified Oswestry Questionnaire (r = − 0.307, p = 0.017) and also with pain intensity according to Visual Analogue Scale (VAS) score (r = − 0.268, p = 0.040) whilst adjusting for age, sex and body mass index (BMI).
Adherence to adrenaline autoinjector prescriptions in patients with anaphylaxis
Authors: Parke Louise , Senders Annemarie Schaeffer , Bindslev-Jensen Carsten , Lassen Annmarie Touborg , Oropeza Athamaica Ruiz , Halken Susanne , Broesby-Olsen Sigurd , Kjær Henrik Fomsgaard , Mortz Charlotte G. 
Published: November 2019

Abstract
This study evaluates adherence to adrenaline autoinjector prescriptions in a cohort of well-characterized anaphylaxis patients. The overall retrieval rate was 76% with the highest rate in patients with severe anaphylaxis. Special attention is needed in patients with unknown elicitors and in young adults, comprising the largest proportion of non-adherent patients.
Trial registration No intervention performed. Retrospective data used with permission from the Danish Data Protection Agency and Regional Committees on Health Research Ethics
Extracellular RNA in systemic lupus erythematosus
Authors: Liu Shanshan , Wang Dandan , Liu Yuan 
Published: November 2019

AbstractSince the discovery of extracellular RNA (exRNA), it has been shown that exRNAs play a significant role as a transducer in intercellular communication and biomarkers in various diseases. Systemic lupus erythematosus (SLE) is a kind of autoimmune disease that has protean manifestations. The survival and long-term prognosis of patients with SLE has improved in these 5–10 years, while disease pathogenesis is still not clear. Many researchers found the changes in exRNA profile, and exRNAs are likely participating in the process of SLE. In this review, we summarize the current profile and function of exRNA in SLE. Circulating miRNAs, in particular, have been identified as biomarkers for SLE diagnosis. We also explore the function of lncRNA in SLE and the potential correlation with disease progression and activity. These studies show that exRNAs may take parts in the process of SLE and some of them can be used as diagnostic tool for SLE.
Patients With Primary Aldosteronism Respond to Unilateral Adrenalectomy With Long-Term Reduction in Salt Intake
Authors: Adolf Christian , Heinrich Daniel A , Holler Finn , Lechner Benjamin , Nirschl Nina , Sturm Lisa , Görge Veronika , Riester Anna , Williams Tracy A , Treitl Marcus , Ladurner Roland , Beuschlein Felix , Reincke Martin 
Published: November 2019

Abstract

Context
High dietary salt intake is known to aggravate arterial hypertension. This effect could be of particular relevance in the setting of primary aldosteronism (PA), which is associated with cardiovascular damage independent of blood pressure levels. The aim of this study was to determine the impact of therapy on salt intake in PA patients.

Patients and Methods
A total of 148 consecutive PA patients (66 with unilateral and 82 with bilateral PA) from the database of the German Conn’s Registry were included. Salt intake was quantified by 24-hour urinary sodium excretion before and after initiation of PA treatment.

Study design
Observational longitudinal cohort study.

Setting
Tertiary care hospital.

Results
At baseline, unilateral PA patients had a significantly higher urinary sodium excretion than patients with bilateral disease (205 vs 178 mmol/d, P = 0.047). Higher urinary sodium excretion correlated with an increased cardiovascular risk profile including proteinuria, impaired lipid, and glucose metabolism and was associated with higher daily doses of antihypertensive drugs to achieve blood pressure control. In unilateral disease, urinary sodium excretion dropped spontaneously to 176 mmol/d (P = 0.012) 1 year after unilateral adrenalectomy and remained low at 3 years of follow-up (174 mmol/d). In contrast, treatment with mineralocorticoid receptor antagonists (MRA) in bilateral PA patients was not associated with a significant change in urinary sodium excretion at follow-up (179 mmol/d vs 183 mmol/d).

Conclusion
PA patients consuming a high-salt diet, estimated based on urinary sodium excretion, respond to adrenalectomy with a significant reduction of salt intake, in contrast to MRA treatment.
The Molecular Basis of Congenital Hypopituitarism and Related Disorders
Authors: Gregory Louise Cheryl , Dattani Mehul Tulsidas 
Published: November 2019

AbstractContextCongenital hypopituitarism (CH) is characterized by the presence of deficiencies in one or more of the 6 anterior pituitary (AP) hormones secreted from the 5 different specialized cell types of the AP. During human embryogenesis, hypothalamo–pituitary (HP) development is controlled by a complex spatio-temporal genetic cascade of transcription factors and signaling molecules within the hypothalamus and Rathke’s pouch, the primordium of the AP.Evidence AcquisitionThis mini-review discusses the genes and pathways involved in HP development and how mutations of these give rise to CH. This may present in the neonatal period or later on in childhood and may be associated with craniofacial midline structural abnormalities such as cleft lip/palate, visual impairment due to eye abnormalities such as optic nerve hypoplasia (ONH) and microphthalmia or anophthalmia, or midline forebrain neuroradiological defects including agenesis of the septum pellucidum or corpus callosum or the more severe holoprosencephaly.Evidence SynthesisMutations give rise to an array of highly variable disorders ranging in severity. There are many known causative genes in HP developmental pathways that are routinely screened in CH patients; however, over the last 5 years this list has rapidly increased due to the identification of variants in new genes and pathways of interest by next-generation sequencing.ConclusionThe majority of patients with these disorders do not have an identified molecular basis, often making management challenging. This mini-review aims to guide clinicians in making a genetic diagnosis based on patient phenotype, which in turn may impact on clinical management.
Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after 131I, γ Radiation and H2O2
Authors: Kyrilli Aglaia , Gacquer David , Detours Vincent , Lefort Anne , Libert Frédéric , Twyffels Laure , Van Den Eeckhaute Laura , Strickaert Aurélie , Maenhaut Carine , De Deken Xavier , Dumont Jacques Emile , Miot Françoise , Corvilain Bernard 
Published: November 2019

AbstractBackgroundThe early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-induced DNA damage response and gene expression in primary cultured human thyrocytes.MethodsFollowing exposure of thyrocytes, in the presence or absence of TSH, to 131I (β radiation), γ radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response.ResultsOverall, the thyrocyte responses following exposure to β or γ radiation and to H2O2 were similar. However, TSH increased 131I-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after 131I exposure.ConclusionsTSH specifically increased 131I-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to 131I.
The cyclin B2/CDK1 complex inhibits separase activity in mouse oocyte meiosis I
Authors: Li Jian , Ouyang Ying-Chun , Zhang Chun-Hui , Qian Wei-Ping , Sun Qing-Yuan 
Published: November 2019

ABSTRACT
Chromosome segregation is driven by separase, activity of which is inhibited by binding to securin and cyclin B1/CDK1. In meiosis, premature separase activity will induce aneuploidy or abolish chromosome segregation owing to the untimely destruction of cohesin. Recently, we have proved that cyclin B2 can compensate for cyclin B1 in CDK1 activation for the oocyte meiosis G2/M transition. In the present study, we identify an interaction between cyclin B2/CDK1 and separase in mouse oocytes. We find that cyclin B2 degradation is required for separase activation during the metaphase I-anaphase I transition because the presence of stable cyclin B2 leads to failure of homologous chromosome separation and to metaphase I arrest, especially in the simultaneous absence of securin and cyclin B1. Moreover, non-phosphorylatable separase rescues the separation of homologous chromosomes in stable cyclin B2-arrested cyclin B1-null oocytes. Our results indicate that cyclin B2/CDK1 is also responsible for separase inhibition via inhibitory phosphorylation to regulate chromosome separation in oocyte meiosis, which may not occur in other cell types.
In vivo cerebellar circuit function is disrupted in an mdx mouse model of Duchenne muscular dystrophy
Authors: Stay Trace L. , Miterko Lauren N. , Arancillo Marife , Lin Tao , Sillitoe Roy V. 
Published: November 2019

ABSTRACT
Duchenne muscular dystrophy (DMD) is a debilitating and ultimately lethal disease involving progressive muscle degeneration and neurological dysfunction. DMD is caused by mutations in the dystrophin gene, which result in extremely low or total loss of dystrophin protein expression. In the brain, dystrophin is heavily localized to cerebellar Purkinje cells, which control motor and non-motor functions. In vitro experiments in mouse Purkinje cells revealed that loss of dystrophin leads to low firing rates and high spiking variability. However, it is still unclear how the loss of dystrophin affects cerebellar function in the intact brain. Here, we used in vivo electrophysiology to record Purkinje cells and cerebellar nuclear neurons in awake and anesthetized female mdx (also known as Dmd) mice. Purkinje cell simple spike firing rate is significantly lower in mdx mice compared to controls. Although simple spike firing regularity is not affected, complex spike regularity is increased in mdx mutants. Mean firing rate in cerebellar nuclear neurons is not altered in mdx mice, but their local firing pattern is irregular. Based on the relatively well-preserved cytoarchitecture in the mdx cerebellum, our data suggest that faulty signals across the circuit between Purkinje cells and cerebellar nuclei drive the abnormal firing activity. The in vivo requirements of dystrophin during cerebellar circuit communication could help explain the motor and cognitive anomalies seen in individuals with DMD.
This article has an associated First Person interview with the first author of the paper.
Quantitative whole-brain 3D imaging of tyrosine hydroxylase-labeled neuron architecture in the mouse MPTP model of Parkinson's disease
Authors: Roostalu Urmas , Salinas Casper B. G. , Thorbek Ditte D. , Skytte Jacob L. , Fabricius Katrine , Barkholt Pernille , John Linu M. , Jurtz Vanessa Isabell , Knudsen Lotte Bjerre , Jelsing Jacob , Vrang Niels , Hansen Henrik H. , Hecksher-Sørensen Jacob 
Published: November 2019

ABSTRACT
Parkinson's disease (PD) is a basal ganglia movement disorder characterized by progressive degeneration of the nigrostriatal dopaminergic system. Immunohistochemical methods have been widely used for characterization of dopaminergic neuronal injury in animal models of PD, including the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. However, conventional immunohistochemical techniques applied to tissue sections have inherent limitations with respect to loss of 3D resolution, yielding insufficient information on the architecture of the dopaminergic system. To provide a more comprehensive and non-biased map of MPTP-induced changes in central dopaminergic pathways, we used iDISCO immunolabeling, light-sheet fluorescence microscopy (LSFM) and deep-learning computational methods for whole-brain three-dimensional visualization and automated quantitation of tyrosine hydroxylase (TH)-positive neurons in the adult mouse brain. Mice terminated 7 days after acute MPTP administration demonstrated widespread alterations in TH expression. Compared to vehicle controls, MPTP-dosed mice showed a significant loss of TH-positive neurons in the substantia nigra pars compacta and ventral tegmental area. Also, MPTP dosing reduced overall TH signal intensity in basal ganglia nuclei, i.e. the substantia nigra, caudate-putamen, globus pallidus and subthalamic nucleus. In contrast, increased TH signal intensity was predominantly observed in limbic regions, including several subdivisions of the amygdala and hypothalamus. In conclusion, mouse whole-brain 3D imaging is ideal for unbiased automated counting and densitometric analysis of TH-positive cells. The LSFM–deep learning pipeline tracked brain-wide changes in catecholaminergic pathways in the MPTP mouse model of PD, and may be applied for preclinical characterization of compounds targeting dopaminergic neurotransmission.