bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Multiple Myeloma with AMG 424, a Novel Anti-CD38/CD3 Bispecific T-cell–recruiting Antibody Optimized for Cytotoxicity and Cytokine Release
Authors: Zuch de Zafra Christina L. , Fajardo Flordeliza , Zhong Wendy , Bernett Matthew J. , Muchhal Umesh S. , Moore Gregory L. , Stevens Jennitte , Case Ryan , Pearson Joshua T. , Liu Siyuan , McElroy Patricia L. , Canon Jude , Desjarlais John R. , Coxon Angela , Balazs Mercedesz , Nolan-Stevaux Olivier 
Published: March 2019

Abstract

Purpose:
Despite advances in the treatment of multiple myeloma, new therapies are needed to induce more profound clinical responses. T-cell–redirected lysis triggered by bispecific antibodies recruiting T cells to cancer cells is a clinically validated mechanism of action against hematologic malignancies and CD38 is a tumor-associated antigen with near-universal expression in multiple myeloma. Thus, an anti-CD38/CD3 bispecific T-cell–recruiting antibody has the potential to be an effective new therapeutic for multiple myeloma.

Experimental Design:
Anti-CD38/CD3 XmAb T-cell–recruiting antibodies with different affinities for CD38 and CD3 were assessed in vitro and in vivo for their redirected T-cell lysis activity against cancer cell lines, their lower levels of cytokine release, and their potency in the presence of high levels of soluble CD38. Select candidates were further tested in cynomolgus monkeys for B-cell depletion and cytokine release properties.

Results:
AMG 424 was selected on the basis of its ability to kill cancer cells expressing high and low levels of CD38 in vitro and trigger T-cell proliferation, but with attenuated cytokine release. In vivo, AMG 424 induces tumor growth inhibition in bone marrow–invasive mouse cancer models and the depletion of peripheral B cells in cynomolgus monkeys, without triggering excessive cytokine release. The activity of AMG 424 against normal immune cells expressing CD38 is also presented.

Conclusions:
These findings support the clinical development of AMG 424, an affinity-optimized T-cell–recruiting antibody with the potential to elicit significant clinical activity in patients with multiple myeloma.
Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer
Authors: Kregel Steven , Malik Rohit , Asangani Irfan A. , Wilder-Romans Kari , Rajendiran Thekkelnaycke , Xiao Lanbo , Vo Josh N. , Soni Tanu , Cieslik Marcin , Fernadez-Salas Ester , Zhou Bing , Cao Xuhong , Speers Corey , Wang Shaomeng , Chinnaiyan Arul M. 
Published: March 2019

Abstract

Purpose:
The bromodomain and extraterminal (BET)-containing proteins (BRD2/3/4) are essential epigenetic coregulators for prostate cancer growth. BRD inhibitors have shown promise for treatment of metastatic castration-resistant prostate cancer (mCRPC), and have been shown to function even in the context of resistance to next-generation AR-targeted therapies such as enzalutamide and abiraterone. Their clinical translation, however, has been limited by off-target effects, toxicity, and rapid resistance.

Experimental Design:
We have developed a series of molecules that target BET bromodomain proteins through their proteasomal degradation, improving efficacy and specificity of standard inhibitors. We tested their efficacy by utilizing prostate cancer cell lines and patient-derived xenografts, as well as several techniques including RNA-sequencing, mass spectroscopic proteomics, and lipidomics.

Results:
BET degraders function in vitro and in vivo to suppress prostate cancer growth. These drugs preferentially affect AR-positive prostate cancer cells (22Rv1, LNCaP, VCaP) over AR-negative cells (PC3 and DU145), and proteomic and genomic mechanistic studies confirm disruption of oncogenic AR and MYC signaling at lower concentrations than BET inhibitors. We also identified increases in polyunsaturated fatty acids (PUFA) and thioredoxin-interacting protein (TXNIP) as potential pharmacodynamics biomarkers for targeting BET proteins.

Conclusions:
Compounds inducing the pharmacologic degradation of BET proteins effectively target the major oncogenic drivers of prostate cancer, and ultimately present a potential advance in the treatment of mCRPC. In particular, our compound dBET-3, is most suited for further clinical development.
Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity
Authors: Aggarwal Rahul R. , Quigley David A. , Huang Jiaoti , Zhang Li , Beer Tomasz M. , Rettig Matthew B. , Reiter Rob E. , Gleave Martin E. , Thomas George V. , Foye Adam , Playdle Denise , Lloyd Paul , Chi Kim N. , Evans Christopher P. , Lara Primo N. , Feng Felix Y. , Alumkal Joshi J. , Small Eric J. 
Published: March 2019

Abstract

Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of AR or an intergenic AR-enhancer locus, and demonstrated lower expression of AR and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of RB1, elevated expression levels of CDKN2A and E2F1, and loss of expression of the AR and AR-responsive genes including TMPRSS2 and NKX3-1. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary.

Implications:
The t-SCNC phenotype is characterized by lack of AR enhancer gain and loss of RB1 function, and demonstrates both interindividual and intraindividual heterogeneity.
Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.
Atrial Fibrillation Catheter Ablation Increases the Left Atrial Pressure
Authors: Park Je-Wook , Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Joung Boyoung , Lee Moon-Hyoung , Hwang Chun , Pak Hui-Nam 
Published: March 2019

Background:
We previously reported that a high left atrial (LA) pressure is associated with LA stiffness and poor rhythm outcomes after de novo catheter ablation of atrial fibrillation. Herein, we investigated whether radiofrequency catheter ablation generally changes the LA pressure among patients undergoing repeat procedures.

Methods:
Among 1848 patients who underwent atrial fibrillation catheter ablation, we measured the LA pressure during sinus rhythm in 1687 patients before the de novo ablation (59±11 years, 72.4% men, 72.8% paroxysmal atrial fibrillation) and in 142 with second procedures. We measured the LA pressure immediately after the transseptal puncture at the beginning of the procedure.

Results:

In the same 142 patients, the degree of LA stiffness, reflected by the LA pulse pressure (LA
pp
), was significantly higher in the second procedure than in the de novo procedure (
P
<0.001). The degree of the LA
pp
increase (ΔLA
pp
) was significantly higher in patients who underwent additional extrapulmonary vein LA ablation than in those who underwent circumferential pulmonary vein isolation alone (
P
=0.010). Extrapulmonary vein LA ablation was independently associated with the ΔLA
pp
(β=5.70 [0.12–11.27];
P
=0.045). An increased LA
pp
during repeat procedures was independently associated with a reduced diastolic function (β=2.01 [0.08–3.93];
P
=0.041) without a worsening symptoms (EuroQol-five dimensions) score, 22.2±17.9 months after the de novo ablation.

Conclusions:
Atrial fibrillation catheter ablation, especially extrapulmonary vein LA ablation, increased the LA stiffness and was associated with a worsening postablation diastolic function. However, the symptom score did not significantly change.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02138695.
High-Resolution Regulatory Maps Connect Vascular Risk Variants to Disease-Related Pathways
Authors: Åkerborg Örjan , Spalinskas Rapolas , Pradhananga Sailendra , Anil Anandashankar , Höjer Pontus , Poujade Flore-Anne , Folkersen Lasse , Eriksson Per , Sahlén Pelin 
Published: March 2019

Background:
Genetic variant landscape of coronary artery disease is dominated by noncoding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct genes both to gain insights into perturbed functions and better assess the risk of disease.

Methods:
In this study, we generated high-resolution genomic interaction maps (≈750 bases) in aortic endothelial, smooth muscle cells and THP-1 (human leukemia monocytic cell line) macrophages stimulated with lipopolysaccharide using Hi-C coupled with sequence capture targeting 25 429 features, including variants associated with coronary artery disease. We also sequenced their transcriptomes and mapped putative enhancers using chromatin immunoprecipitation with an antibody against H3K27Ac.

Results:
The regions interacting with promoters showed strong enrichment for enhancer elements and validated several previously known interactions and enhancers. We detected interactions for 727 risk variants obtained by genome-wide association studies and identified novel, as well as established genes and functions associated with cardiovascular diseases. We were able to assign potential target genes for additional 398 genome-wide association studies variants using haplotype information, thereby identifying additional relevant genes and functions. Importantly, we discovered that a subset of risk variants interact with multiple promoters and their expression levels were strongly correlated.

Conclusions:
In summary, we present a catalog of candidate genes regulated by coronary artery disease–related variants and think that it will be an invaluable resource to further the investigation of cardiovascular pathologies and disease.
Regulation of Intracellular pH is Altered in Cardiac Myocytes of Ovariectomized Rats
Authors: Ibañez Alejandro Martín , Espejo María Sofía , Zavala Maite Raquel , Villa‐Abrille María Celeste , Lofeudo Juan Manuel , Aiello Ernesto Alejandro , De Giusti Verónica Celeste 
Published: March 2019

Background

It is well known that after menopause women are exposed to a greater cardiovascular risk, but the intracellular modifications are not properly described. The sodium/proton exchanger (NHE) and the sodium/bicarbonate cotransporter (NBC) regulate the intracellular pH and, indirectly, the intracellular sodium concentration ([Na
+
]). There are 2 isoforms of NBC in the heart: the electrogenic (1Na
+
/2

; NBCe1) and the electroneutral (1Na
+
/1

; NBCn1). Because NHE and NBCn1 hyperactivity as well as the NBCe1 decreased activity have been associated with several cardiovascular pathologies, the aim of this study was to investigate the potential alterations of the alkalinizing transporters during the postmenopausal period.

Methods and Results
Three‐month ovariectomized rats (OVX) were used. The NHE activity and protein expression are significantly increased in OVX. The NBCe1 activity is diminished, and the NBCn1 activity becomes predominant in OVX rats. p‐Akt levels showed a significant diminution in OVX. Finally, NHE activity in platelets from OVX rats is also higher in comparison to sham rats, resulting in a potential biomarker of cardiovascular diseases.

Conclusions
Our results demonstrated for the first time that in the cardiac ventricular myocytes of OVX rats NHE and NBC isoforms are altered, probably because of the decreased level of p‐Akt, compromising the ionic intracellular homeostasis.
Recent Warming and Freshening of the Norwegian Sea Observed by Argo Data
Authors: Mork Kjell Arne , Skagseth Øystein , Søiland Henrik 
Published: March 2019

Abstract
Climate variability in the Norwegian Sea, comprising the Norwegian and Lofoten Basins, was investigated based upon monthly estimates of ocean heat and freshwater contents using data from Argo floats during 2002–18. Both local air–sea exchange and advective processes were examined and quantified for monthly to interannual time scales. In the recent years, 2011–18, the Norwegian Sea experienced a decoupling of the temperature and salinity, with a simultaneous warming and freshening trend. This was mainly explained by two different processes; reduced ocean heat loss to the atmosphere and advection of fresher Atlantic water into the Norwegian Sea. The local air–sea heat fluxes are important in modifying the ocean heat content, although this relationship varied with time scale and basins. On time scales exceeding 4 months in the Lofoten Basin and 6 months in the Norwegian Basin, the air–sea heat flux explained half or even more of the local ocean heat content change. There were both a short-term and long-term response of the wind forcing on the ocean heat content. The monthly to seasonal response of increased southerly wind cooled and freshened the Norwegian Basin, due to eastward surface Ekman transport, and increased the influence of Arctic Water. However, after about a 1-yr delay the ocean warmed and became saltier due to an increased advection of Atlantic Water into the region. Increased westerly winds decreased the ocean heat content in both cases due to increased transport of Arctic Water into the Norwegian Sea.
The Effect of Partial Automation on Driver Attention: A Naturalistic Driving Study
Authors: Gaspar John , Carney Cher 
Published: March 2019

Objective: This naturalistic driving study investigated how drivers deploy visual attention in a partially automated vehicle. Background: Vehicle automation is rapidly increasing across vehicle fleets. This increase in automation will likely have both positive and negative consequences as drivers learn to use the new technology. Research is needed to understand how drivers interact with partially automated vehicle systems and what impact new technology has on driver attention. Method: Ten participants drove a Tesla Model S for 1 week during their daily commute on a stretch of busy interstate. Drivers were instructed to use Autopilot, a system that provides both lateral and longitudinal control, as much as they felt comfortable while driving on the interstate. Driver-facing video data were recorded and manually reduced to examine glance behavior. Results: Drivers primarily allocated their visual attention between the forward roadway (74% of glance time) and the instrument panel (13%). With partial automation engaged, drivers made longer single glances and had longer maximum total-eyes-off-road time (TEORT) associated with a glance cluster. Conclusion: These results provide a window into the nature of visual attention while driving with partial vehicle automation. The results suggest that drivers may be more willing to execute long, “outlier” glances and clusters of glances to off-road locations with partial automation. The findings highlight several important human factors considerations for partially automated vehicles.
Intelligence and Slave Exports from Africa
Authors: Asongu Simplice A. , Kodila-Tedika Oasis 
Published: March 2019

This article examines the role of cognitive ability or intelligence on slave exports from Africa. We test a hypothesis that countries which were endowed with higher levels of cognitive ability were more likely to experience lower levels of slave exports from Africa probably due to comparatively better capacities to organize, co-operate, oversee and confront slave traders. The investigated hypothesis is valid from alternative specifications involving varying conditioning information sets. The findings are also robust to the control of outliers. JEL: I20, I29, N30
Combining CDP-choline and galantamine: Effects of a selective α7 nicotinic acetylcholine receptor agonist strategy on P50 sensory gating of speech sounds in healthy volunteers
Authors: Choueiry Joelle , Blais Crystal M , Shah Dhrasti , Smith Dylan , Fisher Derek , Illivitsky Vadim , Knott Verner 
Published: March 2019

Background: Schizophrenia (SCZ) patients and relatives have deficits in early cortical sensory gating (SG) typically measured by suppression of electroencephalography-derived P50 event-related potentials (ERPs) in a conditioning-testing (S1–S2) paradigm. Associated with alpha 7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction and shown to be improved with nicotine and α7 nAChR agonists, SG has recently been shown to be improved in low P50 suppressing SCZ patients following acute CDP-choline treatment. Aims: This pilot study in healthy humans assessed the SG effects of an α7 nAChR strategy combining CDP-choline with galantamine, a positive allosteric modulator (PAM) of nAChRs, aimed at increasing and prolonging nicotinic receptor activity. Methods: The combined effect of CDP-choline (500 mg) and galantamine (16 mg) on speech P50 gating indices rP50 (S2/S1) and dP50 (S1–S2) was examined in 30 healthy participants stratified into low and high baseline P50 suppressors in a randomized, double-blind, placebo-controlled and counterbalanced design. Results: In low suppressors, CDP-choline/galantamine (vs. placebo) improved rP50 and dP50 gating, and reduced S2P50 amplitudes. No P50 gating effects were observed in high suppressors; however, CDP-choline/galantamine (vs. placebo) increased their S2P50 amplitudes. Conclusion: Findings from this pilot study with CDP-choline/galantamine in a healthy, SCZ-like surrogate deficient gating sample are consistent with the association of α7 nAChR mechanisms in SG impairment in SCZ and support further research trials with CDP-choline and galantamine targeting sensory processes.
Lansoprazole-Induced Thrombocytopenia in a Critically Ill Patient: A Case Report
Authors: Saad Mohamed , Mitwally Hassan 
Published: March 2019

Introduction: Proton pump inhibitors (PPIs) may rarely cause thrombocytopenia. To our knowledge, only one case of lansoprazole-induced thrombocytopenia has been reported previously. Case: We report a case of a 50-year-old South Asian male who was admitted to the intensive care unit (ICU) after cardiac arrest during general anesthesia for ureteroscopy. During ICU stay, his platelet count dropped from 315×103/µL to 57×103/µL after 5 days of initiation of lansoprazole for stress-ulcer prophylaxis. After excluding other causes of thrombocytopenia; lansoprazole was stopped and his platelets recovered over the next few days. Later exposure to lansoprazole resulted in another drop in his platelet count with subsequent recovery after discontinuation of lansoprazole. A review of his home medications showed that he had been taking pantoprazole prior to hospitalization. Discussion: Thrombocytopenia has been previously reported with different PPIs. In the previously reported lansoprazole-induced thrombocytopenia, the level of certainty was not high due to lack of re-exposure. In the present case, another exposure to lansoprazole, without intention of rechallenge, reproduced the same adverse drug reaction (ADR). Although platelet-reactive antibodies testing was not available to confirm causation in this case, the Naranjo score was 8 which indicated probable causation by lansoprazole. Despite probable lansoprazole-induced thrombocytopenia, our patient had been tolerating pantoprazole. This finding highlights the different effects of individual PPIs on platelet counts in the same patient. Conclusion: Lansoprazole may cause thrombocytopenia. However, patients who develop lansoprazole-induced thrombocytopenia may tolerate other PPIs.
Appropriate Expected Return and the Relationship with Risk
Authors: Maneemaroj Panutat , Lonkani Ravi , Chingchayanurak Chanon 
Published: March 2019

Theoretically, risk-averse investors who expose to higher level of risks should expect to be compensated with more returns. However, prior studies empirically found inconclusive and often counterintuitive results. Motivated by advanced econometric techniques and choices of risk and return recently introduced in literature, we justify and choose the appropriate models and proxies to study the risk and return trade-off pattern in The Stock Exchange of Thailand. Instead of using historical returns mentioned in prior studies, this study chooses the earning ratio to proxy the expected return. For the risk and return trade-off testing model, we employ the ICAPM model with Glosten, Jagannathan and Runkle-GARCH (GJR-GARCH) and GJR with Continuous and Jump Variations (GJR-CJ) as volatility function. Consistent with the theory, results show that the baseline models can explain the positive relationship between risks and returns. By adding the effect of a rare event which can be estimated from the jump process of the data, the forecast accuracy is more improved. In addition, the results find that it is possible that this proxy can be applied in another model which is based on the mean and variance models. Finally, the results from the forecasting model and other models indicate that using an Earning to Price (E/P) ratio as a proxy for expected returns is more appropriate than using the historical return.
Acute electroconvulsive therapy in the elderly with schizophrenia and schizoaffective disorder: a literature review
Authors: Kumagaya David , Halliday Graeme 
Published: March 2019

Objectives: This study reviewed the evidence regarding the efficacy of acute electroconvulsive therapy for primary psychotic conditions in the elderly. Methods: A literature search was performed using the Medline, Embase and Cochrane databases. Results: Acute electroconvulsive therapy resulted in an improvement of psychotic symptoms in almost all elderly patients, a large proportion of whom had treatment-resistant conditions. No electroconvulsive therapy related fatalities or severe medical complications were encountered. Conclusions: Acute electroconvulsive therapy may present a valuable treatment modality for elderly patients with primary psychotic conditions who do not respond adequately to antipsychotic medications.