bluuebunny/crossref_metadata_2025_split huggingface dataset:
High BCR–ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib
Authors: Vigneri Paolo , Stagno Fabio , Stella Stefania , Cupri Alessandra , Forte Stefano , Massimino Michele , Antolino Agostino , Siragusa Sergio , Mannina Donato , Impera Stefana Stella , Musolino Caterina , Malato Alessandra , Mineo Giuseppe , Tomaselli Carmela , Murgano Pamela , Musso Maurizio , Morabito Fortunato , Molica Stefano , Martino Bruno , Manzella Livia , Müller Martin C. , Hochhaus Andreas , Raimondo Francesco Di 
Published: September 2017

Abstract
Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses.
Experimental Design: We correlated BCR–ABL/GUSIS and BCR–ABL/ABL transcripts at diagnosis with the outcome—defined by the 2013 European LeukemiaNet recommendations—of 272 patients newly diagnosed with CML receiving imatinib 400 mg/daily. Applying receiver-operating characteristic curves, we defined BCR–ABL/GUSIS and BCR–ABL/ABL levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS), and overall survival (OS).
Results: With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as “warnings,” 22.4% failed imatinib, and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), seven (2.5%) attributable to disease progression. We found that higher BCR–ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (P &lt; 0.001), FFS (P &lt; 0.001), and EFS (P &lt; 0.001). Elevated BCR–ABL/GUSIS levels were also associated with lower rates of TFS (P = 0.029) but not with OS (P = 0.132). Similarly, high BCR–ABL/ABL levels at diagnosis were associated with inferior rates of OR (P = 0.03), FFS (P = 0.001), and EFS (P = 0.005), but not with TFS (P = 0.167) or OS (P = 0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates.
Conclusions: Our data suggest that high BCR–ABL transcripts at diagnosis measured using GUS as a reference gene identify patients with CML unlikely to benefit from standard-dose imatinib. Clin Cancer Res; 23(23); 7189–98. ©2017 AACR.
Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood–Brain Barrier in Glioblastoma Patients Using an IVIVE–PBPK Modeling Approach
Authors: Li Jing , Wu Jianmei , Bao Xun , Honea Norissa , Xie Youming , Kim Seongho , Sparreboom Alex , Sanai Nader 
Published: September 2017

Abstract
Purpose: AZD1775, a first-in-class, small-molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radiosensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across the human blood–brain barrier (BBB).
Experimental Design: AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 patients with glioblastoma. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a four-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process.
Results: AZD1775 exhibited good tumor penetration in patients with glioblastoma, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII–ABCB1 or MDCKII–ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue.
Conclusions: In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant, driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors. Clin Cancer Res; 23(24); 7454–66. ©2017 AACR.
See related commentary by Peer et al., p. 7437
BMP4 Induces M2 Macrophage Polarization and Favors Tumor Progression in Bladder Cancer
Authors: Martínez Víctor G. , Rubio Carolina , Martínez-Fernández Mónica , Segovia Cristina , López-Calderón Fernando , Garín Marina I. , Teijeira Alicia , Munera-Maravilla Ester , Varas Alberto , Sacedón Rosa , Guerrero Félix , Villacampa Felipe , de la Rosa Federico , Castellano Daniel , López-Collazo Eduardo , Paramio Jesús M. , Vicente Ángeles , Dueñas Marta 
Published: September 2017

Abstract
Purpose: Bladder cancer is a current clinical and social problem. At diagnosis, most patients present with nonmuscle-invasive tumors, characterized by a high recurrence rate, which could progress to muscle-invasive disease and metastasis. Bone morphogenetic protein (BMP)–dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in bladder cancer is still unclear.
Experimental Design: Tumor and normal tissue from 68 patients with urothelial cancer were prospectively collected and analyzed for expression of BMP and macrophage markers. The mechanism of action was assessed in vitro by experiments with bladder cancer cell lines and peripheral blood monocyte–derived macrophages.
Results: We observed BMP4 expression is associated and favored type II macrophage differentiation. In vitro experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from bladder cancer cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL10. Using a series of human bladder cancer patient samples, we also observed increased expression of BMP4 in advanced and undifferentiated tumors in close correlation with epithelial–mesenchymal transition (EMT). However, the p-Smad 1,5,8 staining in tumors showing EMT signs was reduced, due to the increased miR-21 expression leading to reduced BMPR2 expression.
Conclusions: These findings suggest that BMP4 secretion by bladder cancer cells provides the M2 signal necessary for a protumoral immune environment. In addition, the repression of BMPR2 by miR-21 makes the tumor cells refractory to the prodifferentiating actions mediated by BMP ligands, favoring tumor growth. Clin Cancer Res; 23(23); 7388–99. ©2017 AACR.
Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart
Authors: Wu Shu‐Jie , Li Yue‐Chun , Shi Zhe‐Wei , Lin Zhong‐Hao , Rao Zhi‐Heng , Tai Si‐Chao , Chu Mao‐Ping , Li Lei , Lin Jia‐Feng 
Published: September 2017

Background

With chronic ischemia after myocardial infarction, the resulting scar tissue result in electrical and structural remodeling vulnerable to an arrhythmogenic substrate. The cholinergic anti‐inflammatory pathway elicited by vagal nerve via α7 nicotinic acetylcholine receptors (α7‐n
AC
hR) can modulate local and systemic inflammatory responses. Here, we aimed to clarify a novel mechanism for the antiarrhythmogenic properties of vagal nerve during the ischemic cardiomyopathy (
ICM
).

Methods and Results

Left anterior descending artery of adult male Sprague‐Dawley rats was ligated for 4 weeks to develop
ICM
. Western blot revealed that eliciting the cholinergic anti‐inflammatory pathway by nicotine treatment showed a significant reduction in the amounts of collagens, cytokines, and other inflammatory mediators in the left ventricular infarcted border zone via inhibited
NF
‐
κB
activation, whereas it increased the phosphorylated connexin 43. Vagotomy inhibited the anti‐inflammatory, anti‐fibrosis, and anti‐arrhythmogenic effect of nicotine administration. And immunohistochemistry confirmed that the nicotine administration‐induced increase of connexin 43 was located in intercellular junctions. Furthermore nicotine treatment suppressed
NF
‐κB activation in lipopolysaccharide‐stimulated
RAW
264.7 cells, and α‐bungarotoxin (an α7‐n
AC
hR selective antagonist) partly inhibited the nicotine‐treatment effect. In addition, 4‐week nicotine administration slightly improved the cardiac function, increased cardiac parasympathetic tone, decreased the prolonged
QT
c, and decreased the arrhythmia score of programmed electric stimulation‐induced ventricular arrhythmia.

Conclusions

Eliciting the cholinergic anti‐inflammatory pathway exerts anti‐arrhythmogenic effects against
ICM
‐induced ventricular arrhythmia accompanied by downregulation of cytokines, downgenerating of collagens, decrease in sympathetic/parasympathetic ratio, and prevention of the loss of phosphorylated connexin 43 during
ICM
. Our findings may suggest a promising therapy for the generation of
ICM
‐induced ventricular arrhythmia by eliciting the cholinergic anti‐inflammatory pathway.
The Triple Play of Violence in Ismael R. Mbise’s Blood on Our Land
Authors: Mustafa Fawzia 
Published: September 2017

Ismael R. Mbise’s novel Blood on Our Land (1974) re-creates the events known as the Meru Land Case, when in 1951 a group of Wameru from northern Tanganyika petitioned the UN to prevent the British authorities from evicting them from their land. The petition drew international attention to the area for a fleeting moment and, though unsuccessful, it has since entered the national imaginary as an original gesture of peaceful resistance to colonial control. Mbise’s re-creation has also been read as a critical allegory of the implementation of villagization associated with the policies of Ujamaa. The novel does this and more in its brilliant comparative analysis of the vectors of violence within the politics of language, history, and representation, the practices of Indirect Rule and its force of law, and development and its mechanics of ‘modernization’: a triple play.
Power characteristics of variable frequency speed control-based water pumps in open cooling water systems
Authors: Song Yiping , Zhao Jianing 
Published: September 2017

The operational power characteristics of variable frequency speed control-based water pumps in an open cooling water system were studied experimentally. It was found through this research that before and after frequency conversion, the ratio of the power of a particular frequency to the power of the rated frequency of the water pump system shows a third-power relationship. A data fitting method was used to obtain the equation for the power and frequency ratio of the system under the overall operating conditions. The experiment shows that the system height difference has no effect on the basic form of the characteristic equation. Finally, when unified consideration is given to the pump, motor and frequency converter, the calculated power of the water pump system is very close to the actual value.This power characteristic equation contributes to calculations relating to the water pump operational speed regulation in an open cooling water system. Practical application: Variable frequency speed-regulating systems for pumps are applied in open loop water systems, such as those supplying cooling towers. However, the standard cube law which is used to determine the power of the water pump system is inappropriate and exaggerates the potential energy-saving. This study determined a new energy model for the water pump system that can more accurately calculate the total power of the variable frequency controlled water pump when used in open loop systems.
Use of single-view digital breast tomosynthesis (DBT) and ultrasound vs. additional views and ultrasound for the assessment of screen-detected abnormalities: German multi-reader study
Authors: Heywang-Köbrunner Sylvia H , Hacker Astrid , Jänsch Alexander , Kates Ronald , Wulz-Horber Sabina ,   the German Reader Team
Published: September 2017

Background Data on the value of digital breast tomosynthesis (DBT) for further assessment of screen-detected lesions are still limited. Purpose To compare screening mammography, single-view DBT and ultrasound-information (TS) vs. screening mammography, additional views and ultrasound-information (AV) for assessment of screen-detected abnormalities. Material and Methods The use of wide-angle DBT for screen-detected, soft-tissue abnormalities requiring additional views was investigated: 241 cases (206 benign and 35 malignant lesions), verified by histology or two-year follow-up, were read by ten readers as TS and as AV sets, yielding 2410 diagnoses for each set. Readings were randomly sequenced. Results The mean interval between readings was nine weeks (random sequence). Evaluation was breast-based. Overall, in terms of area under receiver operating characteristic (AUC; varying degree of suspicion cutoff), TS and AV readings showed similar performance: for TS, AUC was 0.889 (95% confidence interval [CI] = 0.871–0.907) and for AV, AUC was 0.903 (95% CI = 0.886–0.921). TS readings had slightly higher sensitivity than AV readings (96.9% vs. 95.4%) but lower specificity (50% vs. 58.1%) and more variations between reader performance; absolute false negatives (FN) were reduced in 8/16 readers, equal in 5/16, and increased in only 3/16. Conclusion This study broadly confirms previous data showing equivalence of DBT to AV. However, bias against TS may have occurred since the region of interest was not indicated in the TS set as compared to its obvious identification on the AV set by the selected spot views. A key finding is that reader experience with DBT may be more important than so far reported.
Cardiovascular magnetic resonance detects silent heart disease missed by echocardiography in systemic lupus erythematosus
Authors: Mavrogeni S , Koutsogeorgopoulou L , Markousis-Mavrogenis G , Bounas A , Tektonidou M , Lliossis S-N C , Daoussis D , Plastiras S , Karabela G , Stavropoulos E , Katsifis G , Vartela V , Kolovou G 
Published: September 2017

Background Accurate diagnosis of cardiovascular involvement in systemic lupus erythematosus (SLE) remains challenging, due to limitations of echocardiography. We hypothesized that cardiovascular magnetic resonance can detect cardiac lesions missed by echocardiography in SLE patients with atypical symptoms. Aim To use cardiovascular magnetic resonance in SLE patients with atypical symptoms and investigate the possibility of silent heart disease, missed by echocardiography. Patients/methods From 2005 to 2015, 80 SLE patients with atypical cardiac symptoms/signs (fatigue, mild shortness of breath, early repolarization and sinus tachycardia) aged 37 ± 6 years (72 women/8 men), with normal echocardiography, were evaluated using a 1.5 T system. Left and right ventricular ejection fractions, T2 ratio (oedema imaging) and late gadolinium enhancement (fibrosis imaging) were assessed. Acute and chronic lesions were defined as late gadolinium enhancement-positive plus T2>2 and T2<2, respectively. Lesions were characterized according to late gadolinium enhancement patterns as: diffuse subendocardial, subepicardial and subendocardial/transmural, due to vasculitis, myocarditis and myocardial infarction, respectively. Results Abnormal cardiovascular magnetic resonance findings were identified in 22/80 (27.5%) of SLE patients with normal echocardiography, including 4/22 with recent silent myocarditis, 5/22 with past myocarditis (subepicardial scar in inferolateral wall), 9/22 with past myocardial infarction (six inferior and three anterior subendocardial infarction) and 4/22 with diffuse subendocardial fibrosis due to vasculitis. No correlation between cardiovascular magnetic resonance findings and inflammatory indices was identified. Conclusions Cardiovascular magnetic resonance in SLE patients with atypical cardiac symptoms/signs and normal echocardiography can assess occult cardiac lesions including myocarditis, myocardial infarction and vasculitis that may influence both rheumatic and cardiac treatment.
In vivo induction of neutrophil extracellular traps by Mycobacterium tuberculosis in a guinea pig model
Authors: Filio-Rodríguez Georgina , Estrada-García Iris , Arce-Paredes Patricia , Moreno-Altamirano María M , Islas-Trujillo Sergio , Ponce-Regalado M Dolores , Rojas-Espinosa Oscar 
Published: September 2017

In 2004, a novel mechanism of cellular death, called ‘NETosis’, was described in neutrophils. This mechanism, different from necrosis and apoptosis, is characterized by the release of chromatin webs admixed with microbicidal granular proteins and peptides (NETs). NETs trap and kill a variety of microorganisms. Diverse microorganisms, including Mycobacterium tuberculosis, are NET inducers in vitro. The aim of this study was to examine whether M. tuberculosis can also induce NETs in vivo and if the NETs are bactericidal to the microorganism. Guinea pigs were intradermally inoculated with M. tuberculosis H37Rv, and the production of NETs was investigated at several time points thereafter. NETs were detected as early as 30 min post-inoculation and were clearly evident by 4 h post-inoculation. NETs produced in vivo contained DNA, myeloperoxidase, elastase, histones, ROS and acid-fast bacilli. Viable and heat-killed M. tuberculosis, as well as Mycobacterium bovis BCG were efficient NET inducers, as were unilamellar liposomes prepared with lipids from M. tuberculosis. In vitro, guinea pig neutrophils also produced NETs in response to M. tuberculosis. However, neither the in vivo nor the in vitro-produced NETs were able to kill M. tuberculosis. Nevertheless, in vivo, neutrophils might propitiate recruitment and activation of more efficient microbicidal cells.
Recovery of grip strength and hand dexterity after distal radius fracture: A two-year prospective cohort study
Authors: Bobos Pavlos , Nazari Goris , Lalone Emily A , Grewal Ruby , MacDermid Joy C 
Published: September 2017

Introduction Clinicians often evaluate deficits after an injury by comparing the injured and uninjured side. It is important to understand what deficits occur in hand function after distal radius fracture, how they change over time and their clinical relevance. The purpose of this study was to evaluate the differences in grip strength and hand dexterity between the injured and uninjured hands of patients two years following distal radius fracture. Methods Patients with distal radius fracture were recruited in a specialized hand clinic. Grip strength and hand dexterity were examined bilaterally with a Jamar hand-held dynamometer and with the NK dexterity device at 3, 6, 12 and 24 months’ post-injury respectively. Generalized linear modeling was performed, with age and sex as covariates to assess changes over time, and between sides. Results Patients (n = 154) exhibited mean differences of grip strength between injured and uninjured side at 3 months’ (12.09 kg) and 6 months’ (7.47 kg) follow-up. The associated deficit standardized response means (SRM) were 1.30 and 0.73, respectively. At 2-years follow-up the mean deficit on the injured side was 2.30 kg with SRM = 0.22. One hundred and eleven patients who completed dexterity testing demonstrated small to trivial side to side differences across all time points. Conclusions There were clinically important differences in grip strength between the injured and uninjured hands in patients with a distal radius fracture at 3 and 6 months’ follow-up. However, at 12 and 24 months, grip strength differences were small and of uncertain clinical importance. Trivial to small differences in hand dexterity can be expected between the injured and uninjured hand by 2 years after distal radius fracture.
Impact of a Basal-Bolus Insulin Regimen on Metabolic Control and Risk of Hypoglycemia in Patients With Diabetes Undergoing Peritoneal Dialysis
Authors: Gómez Ana María , Vallejo Santiago , Ardila Freddy , Muñoz Oscar M. , Ruiz Álvaro J. , Sanabria Mauricio , Bunch Alfonso , Morros Elly , Kattah Laura , García-Jaramillo Maira , León-Vargas Fabián 
Published: September 2017

Introduction: Clinical interventional studies in diabetes mellitus usually exclude patients undergoing peritoneal dialysis (PD). This study evaluates the impact of an educational program and a basal-bolus insulin regimen on the blood glucose level control and risk of hypoglycemia in this population. Methods: A before-and-after study was conducted in type 1 and type 2 DM patients undergoing PD at the Renal Therapy Services (RTS) clinic network, Bogota, Colombia. An intervention was instituted consisting of a three-month educational program and a basal-bolus detemir (Levemir, NovoNordisk) and aspart (Novorapid, NovoNordisk) insulin regimen. Prior to the intervention and at the end of treatment were conducted measures of HbA1c levels and continuous glucose monitoring (CGM). Results: Forty-seven patients were recruited. Mean HbA1c level decreased from 8.41% ± 0.83 to 7.68% ± 1.32 (mean difference −0.739, 95% CI −0.419, −1.059; P < .0001). Of subjects, 52% achieved HbA1c levels <7.5% at the end of study. Mean blood glucose level reduced from 194.0 ± 42.5 to 172.9 ± 31.8 mg/dl ( P = .0015) measured by CGM. Significant differences were not observed in incidence of overall ( P = .7739), diurnal ( P = .3701), or nocturnal ( P = .5724) hypoglycemia episodes nor in area under the curve (AUC) <54 mg/dl ( P = .9528), but a reduction in AUC >180 ( P < .01) and AUC >250 ( P = .01) was evidenced for total, diurnal, and nocturnal episodes. Conclusions: An intervention consisting of an educational program and a basal-bolus insulin regimen in type 1 and type 2 diabetes mellitus patients undergoing PD caused a decrease in HbA1c levels, and mean blood glucose levels as measured from CGM with no significant increases in hypoglycemia episodes.
Ectopic ILT3 controls BCR-dependent activation of Akt in B-cell chronic lymphocytic leukemia
Authors: Zurli Vanessa , Wimmer Giuliana , Cattaneo Francesca , Candi Veronica , Cencini Emanuele , Gozzetti Alessandro , Raspadori Donatella , Campoccia Giuseppe , Sanseviero Francesca , Bocchia Monica , Baldari Cosima Tatiana , Kabanova Anna 
Published: September 2017

Key Points
ILT3 is ectopically expressed on mature CLL cells and CLL progenitors in the bone marrow. ILT3 controls the activation of Akt kinase in CLL and contributes to a regulatory network defined by a SHIP-1/Deltex1 axis.