bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery and Optimization of HKT288, a Cadherin-6–Targeting ADC for the Treatment of Ovarian and Renal Cancers
Authors: Bialucha Carl U. , Collins Scott D. , Li Xiao , Saxena Parmita , Zhang Xiamei , Dürr Clemens , Lafont Bruno , Prieur Pierric , Shim Yeonju , Mosher Rebecca , Lee David , Ostrom Lance , Hu Tiancen , Bilic Sanela , Rajlic Ivana Liric , Capka Vladimir , Jiang Wei , Wagner Joel P. , Elliott GiNell , Veloso Artur , Piel Jessica C. , Flaherty Meghan M. , Mansfield Keith G. , Meseck Emily K. , Rubic-Schneider Tina , London Anne Serdakowski , Tschantz William R. , Kurz Markus , Nguyen Duc , Bourret Aaron , Meyer Matthew J. , Faris Jason E. , Janatpour Mary J. , Chan Vivien W. , Yoder Nicholas C. , Catcott Kalli C. , McShea Molly A. , Sun Xiuxia , Gao Hui , Williams Juliet , Hofmann Francesco , Engelman Jeffrey A. , Ettenberg Seth A. , Sellers William R. , Lees Emma 
Published: May 2017

AbstractDespite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell–cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody–drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models—a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030–45. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920
Netrin‐1 Preserves Blood‐Brain Barrier Integrity Through Deleted in Colorectal Cancer/Focal Adhesion Kinase/RhoA Signaling Pathway Following Subarachnoid Hemorrhage in Rats
Authors: Xie Zongyi , Enkhjargal Budbazar , Reis Cesar , Huang Lei , Wan Weifeng , Tang Jiping , Cheng Yuan , Zhang John H. 
Published: May 2017

Background

Netrin‐1 (
NTN
‐1) has been established to be a novel intrinsic regulator of blood‐brain barrier (
BBB
) maintenance. This study was carried out to investigate the potential roles of exogenous
NTN
‐1 in preserving
BBB
integrity after experimental subarachnoid hemorrhage (
SAH
) as well as the underlying mechanisms of its protective effects.

Methods and Results

A total of 309 male Sprague‐Dawley rats were subjected to an endovascular perforation model of
SAH
. Recombinant
NTN
‐1 was administered intravenously 1 hour after
SAH
induction.
NTN
‐1 small interfering
RNA
or Deleted in Colorectal Cancer small interfering
RNA
was administered intracerebroventricular at 48 hours before
SAH
. Focal adhesion kinase inhibitor was administered by intraperitoneal injection at 1 hour prior to
SAH
. Neurological scores, brain water content,
BBB
permeability, RhoA activity, Western blot, and immunofluorescence staining were evaluated. The expression of endogenous
NTN
‐1 and its receptor Deleted in Colorectal Cancer were increased after
SAH
. Administration of exogenous
NTN
‐1 significantly reduced brain water content and
BBB
permeability and ameliorated neurological deficits at 24 and 72 hours after
SAH
. Exogenous
NTN
‐1 treatment significantly promoted phosphorylated focal adhesion kinase activation and inhibited RhoA activity, as well as upregulated the expression of
ZO
‐1 and Occludin. Conversely, depletion of endogenous
NTN
‐1 aggravated
BBB
breakdown and neurological impairments at 24 hours after
SAH
. The protective effects of
NTN
‐1 at 24 hours after
SAH
were also abolished by pretreatment with Deleted in Colorectal Cancer small interfering
RNA
and focal adhesion kinase inhibitor.

Conclusions

NTN
‐1 treatment preserved
BBB
integrity and improved neurological functions through a Deleted in Colorectal Cancer/focal adhesion kinase/RhoA signaling pathway after
SAH
. Thus,
NTN
‐1 may serve as a promising treatment to alleviate early brain injury following
SAH
.
Factors Associated With Ischemic Stroke Survival and Recovery in Older Adults
Authors: Winovich Divya Thekkethala , Longstreth William T. , Arnold Alice M. , Varadhan Ravi , Zeki Al Hazzouri Adina , Cushman Mary , Newman Anne B. , Odden Michelle C. 
Published: May 2017

Background and Purpose—
Little is known about factors that predispose older adults to poor recovery after a stroke. In this study, we sought to evaluate prestroke measures of frailty and related factors as markers of vulnerability to poor outcomes after ischemic stroke.

Methods—
In participants aged 65 to 99 years with incident ischemic strokes from the Cardiovascular Health Study, we evaluated the association of several risk factors (frailty, frailty components, C-reactive protein, interleukin-6, and cystatin C) assessed before stroke with stroke outcomes of survival, cognitive decline (≥5 points on Modified Mini-Mental State Examination), and activities of daily living decline (increase in limitations).

Results—
Among 717 participants with incident ischemic stroke with survival data, slow walking speed, low grip strength, and cystatin C were independently associated with shorter survival. Among participants <80 years of age, frailty and interleukin-6 were also associated with shorter survival. Among 509 participants with recovery data, slow walking speed, and low grip strength were associated with both cognitive and activities of daily living decline poststroke. C-reactive protein and interleukin-6 were associated with poststroke cognitive decline among men only. Frailty status was associated with activities of daily living decline among women only.

Conclusions—
Markers of physical function—walking speed and grip strength—were consistently associated with survival and recovery after ischemic stroke. Inflammation, kidney function, and frailty also seemed to be determinants of survival and recovery after an ischemic stroke. These markers of vulnerability may identify targets for differing pre and poststroke medical management and rehabilitation among older adults at risk of poor stroke outcomes.
Subarachnoid Hemorrhage Severely Impairs Brain Parenchymal Cerebrospinal Fluid Circulation in Nonhuman Primate
Authors: Goulay Romain , Flament Julien , Gauberti Maxime , Naveau Michael , Pasquet Nolwenn , Gakuba Clement , Emery Evelyne , Hantraye Philippe , Vivien Denis , Aron-Badin Romina , Gaberel Thomas 
Published: May 2017

Background and Purpose—
Subarachnoid hemorrhage (SAH) is a devastating form of stroke with neurological outcomes dependent on the occurrence of delayed cerebral ischemia. It has been shown in rodents that some of the mechanisms leading to delayed cerebral ischemia are related to a decreased circulation of the cerebrospinal fluid (CSF) within the brain parenchyma. Here, we evaluated the cerebral circulation of the CSF in a nonhuman primate in physiological condition and after SAH.

Methods—

We first evaluated in physiological condition the circulation of the brain CSF in
Macaca
facicularis
, using magnetic resonance imaging of the temporal DOTA-Gd distribution after its injection into the CSF. Then, animals were subjected to a minimally invasive SAH before an MRI evaluation of the impact of SAH on the brain parenchymal CSF circulation.

Results—
We first demonstrate that the CSF actively penetrates the brain parenchyma. Two hours after injection, almost the entire brain is labeled by DOTA-Gd. We also show that our model of SAH in nonhuman primate displays the characteristics of SAH in humans and leads to a dramatic impairment of the brain parenchymal circulation of the CSF.

Conclusions—
The CSF actively penetrates within the brain parenchyma in the gyrencephalic brain, as described for the glymphatic system in rodent. This parenchymal CSF circulation is severely impaired by SAH.
Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation
Authors: Desilles Jean-Philippe , Syvannarath Varouna , Ollivier Véronique , Journé Clément , Delbosc Sandrine , Ducroux Célina , Boisseau William , Louedec Liliane , Di Meglio Lucas , Loyau Stéphane , Jandrot-Perrus Martine , Potier Louis , Michel Jean-Baptiste , Mazighi Mikael , Ho-Tin-Noé Benoit 
Published: May 2017

Background and Purpose—
Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury.

Methods—
Normoglycemic and streptozotocin-treated hyperglycemic rats were subjected to transient middle cerebral artery occlusion. Infarct growth and brain perfusion were assessed by magnetic resonance imaging. Markers of platelet, coagulation, and neutrophil activation were measured in brain homogenates and plasma. Downstream microvascular thromboinflammation (DMT) was investigated by intravital microscopy.

Results—
Hyperglycemic rats had an increased infarct volume with an increased blood–brain barrier disruption and hemorrhagic transformation rate compared with normoglycemic rats. Magnetic resonance imaging scans revealed that hyperglycemia enhanced and accelerated lesion growth and was associated with hemorrhagic transformation originating from territories that were still not completely reperfused at 1 hour after middle cerebral artery recanalization. Intravital microscopy and analysis of brain homogenates showed that DMT began immediately after middle cerebral artery occlusion and was exacerbated by hyperglycemia. Measurement of plasma serotonin and matrix metalloproteinase-9 indicated that platelets and neutrophils were preactivated in hyperglycemic rats. Neutrophils from hyperglycemic diabetic patients showed increased adhesion to endothelial cells as compared with neutrophils from normoglycemic donors in flow chamber experiments.

Conclusions—
We show that hyperglycemia primes the thromboinflammatory cascade, thus, amplifying middle cerebral artery occlusion–induced DMT. DMT exacerbation in hyperglycemic rats impaired reperfusion and precipitated neurovascular damage, blood–brain barrier disruption, and hemorrhagic transformation. Our results designate DMT as a possible target for reduction of the deleterious impact of hyperglycemia in acute ischemic stroke.
Energy Spectra and Inertia–Gravity Waves in Global Analyses
Authors: Žagar Nedjeljka , Jelić Damjan , Blaauw Marten , Bechtold Peter 
Published: May 2017

Abstract
Several decades after E. Dewan predicted that the shallowing of the atmospheric energy spectrum in mesoscale is produced by the inertia–gravity (IG) waves, global analyses have reached the resolution at which the IG waves across many scales are resolved. The authors discuss the spatial filtering method based on the Hough harmonics that provides the temperature and wind perturbations associated with the IG waves in global analysis data. The method is applied to the ECMWF interim reanalysis and the operational 2014–16 analysis fields. The derived spectrum of IG wave energy is divided into three regimes: a part associated with the large-scale unbalanced circulations that has a slope close to −1 for zonal wavenumbers 1 ≤ k ≤ 6, a synoptic-scale range between 3000 and around 500 km (7 ≤ k ≲ 35) that is characterized by a nearly −5/3 slope, and a mesoscale range below 500 km where the slope of the IG energy spectrum in the 2015/16 analyses is steeper. In contrast, the energy spectrum of the Rossby waves has a −3 slope for all zonal wavenumbers k &gt; 6. Presented results suggest that energy associated with the IG modes exceeds the level of energy associated with the Rossby waves around zonal wavenumber 35. The exact wavenumber depends on the season and considered atmospheric depth and it is suggested as a cutoff scale for studies of gravity waves.
Cold agglutinin disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care utilization
Authors: Mullins Megan , Jiang Xiaohui , Bylsma Lauren C. , Fryzek Jon P. , Reichert Heidi , Chen Evan C. , Kummar Shivaani , Rosenthal Adam 
Published: May 2017

Key PointsThis study demonstrates the severity of anemia and relapsing nature of CAD over time, even after administration of multiple therapies. The majority of CAD patients will at some point in their disease course manifest severe disease necessitating transfusion.
Long-lived plasma cells in human bone marrow can be either CD19+ or CD19–
Authors: Brynjolfsson Siggeir F. , Mohaddes Maziar , Kärrholm Johan , Wick Mary-Jo 
Published: May 2017

Key PointsLong-lived plasma cells secreting vaccinia-specific antibodies are detected in human bone marrow >35 years after the eradication of smallpox. Long-lived plasma cells secreting vaccinia-specific antibodies are still able to express the B-lymphocyte antigen CD19.
Smoking, alcohol and drug use in youth and adults with attention-deficit hyperactivity disorder
Authors: Osland Sydney , Hirsch Lauren , Pringsheim Tamara 
Published: May 2017

BackgroundPrevious research suggests a relationship between attention-deficit hyperactivity disorder (ADHD) and smoking, alcohol and illicit drug use, however most studies have focused on adolescents or young adults, or clinically ascertained samples.AimsTo analyse population-based data on the relationship between ADHD and at-risk health behaviours in adolescents and adults.MethodData were derived from a Statistics Canada population-based health survey. The association between the diagnosis of ADHD and smoking, alcohol use, and illicit drug use was examined.ResultsIndividuals with ADHD started smoking at a younger age. They consumed more alcoholic drinks on drinking days, and women with ADHD were more likely to engage in binge drinking. Women over the age of 25 and men with ADHD were more likely to meet alcohol-dependence lifetime criteria. People with ADHD were at a greater risk of drug misuse and dependence.ConclusionsPeople with ADHD are more likely to partake in at-risk behaviours.
Thoracic Epidural Analgesia With Levobupivacaine Reduces Remifentanil and Propofol Consumption Evaluated by Closed-Loop Titration Guided by the Bispectral Index: A Double-Blind Placebo-Controlled Study
Authors: Dumans-Nizard Virginie , Le Guen Morgan , Sage Edouard , Chazot Thierry , Fischler Marc , Liu Ngai 
Published: May 2017

BACKGROUND:
Thoracic epidural analgesia (TEA) combined with general anesthesia decreases anesthetic requirements by half when hemodynamic criteria are used for the titration of analgesia. We therefore determined the impact of TEA on anesthetic requirements, when a closed-loop controller was used allowing the automated coadministration of propofol-remifentanil guided solely by the Bispectral index.

METHODS:
This single-center double-blind study enrolled patients scheduled for elective posterolateral thoracotomy using TEA. Patients were randomly assigned to receive a bolus followed by a continuous infusion of levobupivacaine 0.5% (levo group) or saline 0.9% solution (saline group). General anesthesia was performed by the same automated controller. Stroke volume optimization guided by an esophageal Doppler probe was performed before randomization. The primary outcome variable was the amount of remifentanil delivered by the automated controller between skin incision and closure. Major arterial hypotension was recorded. Data are presented as medians [interquartile range] or number (%)

RESULTS:
Nineteen adult patients per group completed the study. At similar depth of anesthesia evaluated by the percentage of time with the Bispectral index in the range 40–60 (85 [77–88] vs 83 [72–87]; P = .39), patients with neuraxial block required less remifentanil (0.15 [0.10–0.20] vs 0.23 [0.14–0.25], µg·kg−
1·min−
1; P = .03) and propofol (4.3 [3.7–4.9] vs 5.7 [4.6–7.3] mg·kg−
1·h−1; P = .005). Major arterial hypotension was similar in both groups (6 [32%] vs 5 [25%]; P = .46; levo versus saline group, respectively).

CONCLUSIONS:
Epidurally administered levobupivacaine allowed a decrease by one-third of remifentanil requirement. After stroke volume optimization, major arterial hypotension was similar between groups.
Perineural Dexmedetomidine Is More Effective Than Clonidine When Added to Local Anesthetic for Supraclavicular Brachial Plexus Block: A Systematic Review and Meta-analysis
Authors: El-Boghdadly Kariem , Brull Richard , Sehmbi Herman , Abdallah Faraj W. 
Published: May 2017

BACKGROUND:
Clonidine, an α-2 agonist, has long been used as a local anesthetic adjunct with proven efficacy to prolong peripheral nerve block duration. Dexmedetomidine, a newer α-2 agonist, has a more favorable pharmacodynamic and safety profile; however, data comparing its efficacy as an adjunct to that of clonidine are inconsistent. We sought to compare the clinical efficacy of these 2 α-2 agonists by examining their effects on peripheral nerve block characteristics for upper extremity surgery.

METHODS:
A preliminary search found that the overwhelming majority of randomized controlled trials comparing perineural dexmedetomidine to clonidine for upper extremity surgery were in the setting of supraclavicular brachial plexus block (SCB). Therefore, we performed a systematic review and meta-analysis of randomized controlled trials comparing dexmedetomidine with clonidine as perineural adjuncts to single-injection SCB. Sensory and motor block duration and onset, analgesic duration, α-2 agonist side effects, and block complications were analyzed. Sensory block duration was designated as a primary outcome. Data were combined using random-effects modeling, and ratio-of-means was used to analyze the results.

RESULTS:
A total of 868 patients from 14 clinical studies were included in the analysis. Compared with clonidine, dexmedetomidine prolonged the duration (ratio of means [95% confidence interval {CI}]) of sensory block by an estimate of 1.2 (1.2–1.3; P< .00001). It also prolonged the duration (ratio of means [99% CI]) of motor block by an estimate of 1.2 (1.1–1.3; P < .00001), and analgesia by an estimate of 1.2 (1.1–1.3; P < .00001). It also hastened the onset of sensory block by an estimate of 0.9 (0.8–1.0; P < .00001) and motor block by an estimate of 0.9 (0.9–1.0; P = .002). Dexmedetomidine was associated with an increased odds ratio (99% CI) of transient bradycardia by an estimate of 7.4 (1.3–40.8; P = .003) and postoperative sedation by an estimate of 11.8 (1.9–73.6; P = .0005). There were no differences in other α-2 agonist–related side effects or block-related complications.

CONCLUSIONS:
Compared with clonidine as a local anesthetic adjunct for single-injection SCB, perineural dexmedetomidine enhances sensory, motor, and analgesic block characteristics. These benefits should be weighed against the increased risk of transient bradycardia.
Postoperative High-Sensitivity Troponin and Its Association With 30-Day and 12-Month, All-Cause Mortality in Patients Undergoing On-Pump Cardiac Surgery
Authors: Mauermann Eckhard , Bolliger Daniel , Fassl Jens , Grapow Martin , Seeberger Esther E. , Seeberger Manfred D. , Filipovic Miodrag , Lurati Buse Giovanna A. L. 
Published: May 2017

BACKGROUND:
Troponin T is a predictor of cardiac morbidity and mortality after cardiac surgery with most data examining fourth generational troponin T assays. We hypothesize that postoperative high-sensitivity troponin T (hsTnT) measured in increments of the upper limit of the norm independently predicts 30-day all-cause mortality.

METHODS:
We included consecutive patients undergoing on-pump cardiac surgery from February 2010 to March 2012 in a prospective cohort that measured hsTnT at 0600 of the first and second postoperative day. Our primary end point was 30-day, all-cause mortality. The secondary end point was 12-month, all-cause mortality in patients surviving the first 30 days. We divided hsTnT into 5 predetermined categorizes based on the upper limit of the norm (ULN). We used Cox regression to examine an association of hsTnT independent of the EuroSCORE II at both 30 days as well as at 12 months in patients surviving the first 30 days. We assessed the area under the receiver operating characteristics curve and the net reassignment improvement for examining the benefit of adding of hsTnT to the EuroSCORE II for prognostication and restratification of 30-day, all-cause mortality.

RESULTS:
We included 1122 of 1155 eligible patients (75% male; mean age 66 ± 11 years). We observed 58 (5.2%) deaths at 30 days and another 35 (3.4%) deaths at 12 months in patients surviving 30 days. HsTnT categorized by ULN exhibited a graded response for the mortality. Furthermore, hsTnT remained an independent predictor of all-cause mortality at 30 days (adjusted hazard ratio 1.019 [1.014–1.024] per 10-fold increase in ULN) as well as at 12 months (adjusted hazard ratio 1.019 [1.007–1.032]) in patients surviving the first 30 days. The addition of hsTnT to the EuroSCORE II significantly increased the area under the receiver operating characteristics curve (area under curve: 0.816 [95% confidence interval, 0.754–0.878] versus area under curve: 0.870 [95% confidence interval, 0.822–0.917], respectively; P = .012). Finally, adding hsTnT to the EuroSCORE II improved restratification by the net reassignment improvement, primarily by improving rule-out of events.

CONCLUSIONS:
This analysis suggests that, similar to previous assays, higher postoperative concentrations of hsTnT are independently associated with all-cause mortality in patients undergoing on-pump cardiac surgery.