bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL
Authors: Jones Luke , Richmond Jennifer , Evans Kathryn , Carol Hernan , Jing Duohui , Kurmasheva Raushan T. , Billups Catherine A. , Houghton Peter J. , Smith Malcolm A. , Lock Richard B. 
Published: January 2017

Abstract
Purpose: Robust preclinical models of pediatric acute lymphoblastic leukemia (ALL) are essential in prioritizing promising therapies for clinical assessment in high-risk patients. Patient-derived xenograft (PDX) models of ALL provide a clinically relevant platform for assessing novel drugs, with efficacy generally assessed by enumerating circulating human lymphoblasts in mouse peripheral blood (PB) as an indicator of disease burden. While allowing indirect measurement of disease burden in real time, this technique cannot assess treatment effects on internal reservoirs of disease. We explore benefits of bioluminescence imaging (BLI) to evaluate drug responses in ALL PDXs, compared with PB monitoring. BLI-based thresholds of drug response are also explored.
Experimental Design: ALL PDXs were lentivirally transduced to stably express luciferase and green fluorescent protein. In vivo PDX responses to an induction-type regimen of vincristine, dexamethasone, and L-asparaginase were assessed by BLI and PB. Residual disease at day 28 after treatment initiation was assessed by flow cytometric analysis of major organs. BLI and PB were subsequently used to evaluate efficacy of the Bcl-2 inhibitor venetoclax.
Results: BLI considerably accelerated and enhanced detection of leukemia burden compared with PB and identified sites of residual disease during treatment in a quantitative manner, highlighting limitations in current PB-based scoring criteria. Using BLI alongside enumeration of human lymphoblasts in PB and bone marrow, we were able to redefine response criteria analogous to the clinical setting.
Conclusions: BLI substantially improves the stringency of preclinical drug testing in pediatric ALL PDXs, which will likely be important in prioritizing effective agents for clinical assessment. Clin Cancer Res; 23(14); 3744–55. ©2017 AACR.
Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4
Authors: Sowalsky Adam G. , Kissick Haydn T. , Gerrin Sean J. , Schaefer Rachel J. , Xia Zheng , Russo Joshua W. , Arredouani M. Simo , Bubley Glenn J. , Sanda Martin G. , Li Wei , Ye Huihui , Balk Steven P. 
Published: January 2017

Abstract
Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established.
Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture–microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities.
Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci.
Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention. Clin Cancer Res; 23(14); 3823–33. ©2017 AACR.
PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers
Authors: Packer Leisl M. , Geng Xinyan , Bonazzi Vanessa F. , Ju Robert J. , Mahon Clare E. , Cummings Margaret C. , Stephenson Sally-Anne , Pollock Pamela M. 
Published: January 2017

Abstract
Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer. Endometrial cancers display hyperactivation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA, and PIK3R1. The FGFR2 and PI3K pathways, have emerged as potential therapeutic targets in endometrial cancer. Activation of the PI3K pathway is seen in more than 90% of FGFR2mutant endometrial cancers. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719. We assessed synergy in three FGFR2mutant endometrial cancer cell lines (AN3CA, JHUEM2, and MFE296), and the combination of BGJ398 and GDC-0941 or BYL719 showed strong synergy. A significant increase in cell death and decrease in long-term survival was seen when PI3K inhibitors were combined with BGJ398. Importantly, these effects were seen at low concentrations correlating to only partial inhibition of AKT. The combination of BGJ398 and GDC-0941 showed tumor regressions in vivo, whereas each drug alone only showed moderate tumor growth inhibition. BYL719 alone resulted in increased tumor growth of AN3CA xenografts but in combination with BGJ398 resulted in tumor regression in both AN3CA- and JHUEM2-derived xenografts. These data provide evidence that subtherapeutic doses of PI3K inhibitors enhance the efficacy of anti-FGFR therapies, and a combination therapy may represent a superior therapeutic treatment in patients with FGFR2mutant endometrial cancer. Mol Cancer Ther; 16(4); 637–48. ©2017 AACR.
Reactive Oxygen Species–Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies
Authors: Makena Monish R. , Koneru Balakrishna , Nguyen Thinh H. , Kang Min H. , Reynolds C. Patrick 
Published: January 2017

AbstractT-cell lymphoid malignancies (TCLM) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitor romidepsin and the synthetic cytotoxic retinoid fenretinide both have achieved durable clinical responses in T-cell lymphomas as single agents. We investigated the potential for using these two agents in combination in TCLMs. We demonstrated cytotoxic synergy between romidepsin and fenretinide in 15 TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for nonmalignant cells (fibroblasts and blood mononuclear cells). In vivo, romidepsin + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous and disseminated TCLM xenograft models than single-agent romidepsin or fenretinide + ketoconazole. Fenretinide + romidepsin caused a reactive oxygen species (ROS)–dependent increase in proapoptotic proteins (Bim, tBid, Bax, and Bak), apoptosis, and inhibition of HDAC enzymatic activity, which achieved a synergistic increase in histone acetylation. The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + romidepsin were abrogated by antioxidants (vitamins C or E). Romidepsin + fenretinide activated p38 and JNK via ROS, and knockdown of p38 and JNK1 significantly decreased the synergistic cytotoxicity. Romidepsin + fenretinide also showed synergistic cytotoxicity for B-lymphoid malignancy cell lines, but did not increase ROS, acetylation of histones, activation of p38 + JNK, or cytotoxicity in nonmalignant cells. Romidepsin + fenretinide achieved synergistic activity in preclinical models of TCLMs, but not in nonmalignant cells, via a novel molecular mechanism. These data support conducting clinical trials of romidepsin + fenretinide in relapsed and refractory TCLMs. Mol Cancer Ther; 16(4); 649–61. ©2017 AACR.
Use of Intravenous Recombinant Tissue Plasminogen Activator in Patients With Acute Ischemic Stroke Who Take Non–Vitamin K Antagonist Oral Anticoagulants Before Stroke
Authors: Xian Ying , Federspiel Jerome J. , Hernandez Adrian F. , Laskowitz Daniel T. , Schwamm Lee H. , Bhatt Deepak L. , Smith Eric E. , Fonarow Gregg C. , Peterson Eric D. 
Published: January 2017

Background:
Intravenous rt-PA (recombinant tissue-type plasminogen activator) is effective in improving outcomes in ischemic stroke; however, there are few data on the use of rt-PA in patients who are receiving a non–vitamin K antagonist oral anticoagulant (NOAC).

Methods:
Using data from the American Heart Association Get With The Guidelines-Stroke Registry, we examined the outcomes of use of thrombolytic therapy in patients with ischemic stroke who received anticoagulation with NOACs versus those on warfarin (international normalized ratio <1.7) or not on anticoagulation from 1289 registry hospitals between October 2012 and March 2015.

Results:

Of 42 887 patients with ischemic stroke treated with intravenous rt-PA within 4.5 hours, 251 were taking NOACs (dabigatran 87, rivaroxaban 129, and apixaban 35) before their stroke, 1500 were taking warfarin, and 41 136 were on neither. Patients on NOACs or warfarin were older, had more comorbid conditions, and experienced more severe strokes than did those who were not on anticoagulation (median National Institutes of Health Stroke Scale 12, 13, and 9, respectively). Unadjusted rates of symptomatic intracranial hemorrhage in the NOAC, warfarin, and none groups were 4.8%, 4.9%, and 3.9%, respectively (
P
=0.11). In comparison with those not on anticoagulation, the adjusted odds ratio for symptomatic intracranial hemorrhage for those on NOACs was 0.92 (95% confidence interval, 0.51–1.65) and for those on warfarin the adjusted odds ratio was 0.85 (95% confidence interval, 0.66–1.10). There were also no significant differences in the risk for life-threatening/serious systemic hemorrhage, any rt-PA complication, in-hospital mortality, and modified Rankin Scale at discharge across 3 groups. Similar results were also found after propensity score matching.

Conclusions:
Although experience of using rt-PA in patients with ischemic stroke on a NOAC is limited, these preliminary observations suggest that rt-PA appears to be reasonably well tolerated without prohibitive risks for adverse events among selected NOAC-treated patients. Future studies should evaluate the safety and efficacy of intravenous rt-PA in patients with ischemic stroke who are taking NOACs.
Estimating Vertical Motion Profile Top-Heaviness: Reanalysis Compared to Satellite-Based Observations and Stratiform Rain Fraction
Authors: Back Larissa E. , Hansen Zachary , Handlos Zachary 
Published: January 2017

Abstract
A method for representing geographic variability in vertical motion profile top-heaviness in reanalysis data is introduced. The results from this method are compared to a satellite-based method for estimating top-heaviness of vertical motion profiles over the oceans. The satellite-based method utilizes basis functions, idealized or from reanalysis, along with scatterometer wind convergence data and rainfall to estimate the top-heaviness of the vertical motion profile. Results from the two methods of estimating top-heaviness are significantly correlated. Both estimates of top-heaviness are compared to stratiform, shallow, and convective rain fraction. Findings show geographic variability in stratiform rain fraction is not well correlated with estimated profile top-heaviness. Shallow rain fraction is not variable enough to explain this finding. The results may be due to geographic variations in the shape of convective or stratiform heating profiles. An example is given of how variations in convective heating profiles could lead to a region with more stratiform rain having a more bottom-heavy profile.
Formation Mechanisms of the Pacific–North American Teleconnection with and without Its Canonical Tropical Convection Pattern
Authors: Dai Ying , Feldstein Steven B. , Tan Benkui , Lee Sukyoung 
Published: January 2017

The mechanisms that drive the Pacific–North American (PNA) teleconnection pattern with and without its canonical tropical convection pattern are investigated with daily ERA-Interim and NOAA OLR data (the former pattern is referred to as the convective PNA, and the latter pattern is referred to as the nonconvective PNA). Both the convective and nonconvective positive PNA are found to be preceded by wave activity fluxes associated with a Eurasian wave train. These wave activity fluxes enter the central subtropical Pacific, a location that is favorable for barotropic wave amplification, just prior to the rapid growth of the PNA. The wave activity fluxes are stronger for the positive nonconvective PNA, suggesting that barotropic amplification plays a greater role in its development. The negative convective PNA is also preceded by a Eurasian wave train, whereas the negative nonconvective PNA grows from the North Pacific contribution to a circumglobal teleconnection pattern. Driving by high-frequency eddy vorticity fluxes is largest for the negative convective PNA, indicating that a positive feedback may be playing a more dominant role in its development. The lifetimes of convective PNA events are found to be longer than those of nonconvective PNA events, with the former (latter) persisting for about three (two) weeks. Furthermore, the frequency of the positive (negative) convective PNA is about 40% (60%) greater than that of the positive (negative) nonconvective PNA.
Is the Influence of Stability on the Sea Surface Heat Flux Important?
Authors: Mahrt L. , Hristov Tihomir 
Published: January 2017

AbstractObservations of the heat flux over the open sea and in the coastal zone are analyzed to reexamine the relation of the heat flux to the air–sea temperature difference and wind speed. The study begins by examining problems with different methods for estimating the air–sea temperature difference. The difference between the air and within-water temperature is found to be most suitable for one dataset, while the difference between the air and the radiometrically measured sea surface temperature must be used for the second dataset. On average, the heat flux is linearly proportional to the product of the air–sea temperature difference and wind speed corresponding to approximately constant transfer coefficient for heat CH. Deviations of the heat flux from this simple relationship were generally weakly related or unrelated to the surface bulk Richardson number Rb, even for the coastal zone site. Similar results are also found for the moisture flux. In contrast to the general success of constant transfer coefficient for heat, CH plotted directly as a function of Rb is systematically related to the square root of Rb. The role of the wind speed as a shared variable between CH and Rb also predicts such a square root dependence, suggesting that the relationship could be largely due to self-correlation, which is also supported by a nominal study of self-correlation. However, confident isolation of the influences of stability, self-correlation, uncertainties in the air–sea temperature difference, and other physics requires more extensive data.
Voltage Profile and Power Loss in a Uniform Distribution Feeder
Authors: Abdel-Salam T. S. , Hackam R. , Chikhani A. Y. 
Published: January 2017

Voltage profile and power loss in a uniform distribution feeder A teaching topic suitable for inclusion in a power systems course is described. The dependence of voltage profile and power loss reduction of a uniformly distributed feeder, on the parameters of (1) location of compensating capacitor, (2) rating of capacitor, (3) load level and (4) power factor is demonstrated.
The Homeless Mentally Ill: Myths and Realities
Authors: Hamid Walid Abdul , Wykes Til , Stansfeld Stephen 
Published: January 2017

This literature review summarises the historical background of homelessness. It suggests that the current view of homeless people as chronic mentally ill is the latest phase in a series of the different ways in which society has perceived and labelled the homeless. We have argued that homelessness is a product of the lack of housing provision to the poorest section of society and that the psychiatric needs of many of the homeless might be a direct result of poverty and homelessness. This review also highlights difficulties in interpreting data produced by surveys of homeless people. These difficulties include the multiple definitions of homelessness used and also the major methodological errors which limit the usefulness of their findings. In particular sampling methods used may have overestimated the more visible part of the homeless population, overestimating the levels of psychiatric morbidity. Even if these limitations are ignored the data produced by these studies do not allow planning of effective mental health services for homeless people as their results depend mainly on diagnostic classification rather than disability or need. What is required is a study of needs where the appropriateness of particular services is defined, the sampling method is explicit and the definitions of homelessness are precise and consistent.
The Impact of Unemployment On Psychosomatic Symptoms and Mental Well-Being
Authors: Vnamäki Heimo , Koskela Kaj , Niskanen Leo 
Published: January 2017

The relationship between psychosomatic symptoms and mental well-being among unemployed (N = 132) and employed (N = 187) personnel of two similar wood-processing factories was studied. Mental well-being was measured by means of the 12-item General Health Questionnaire (GHQ-score) and the 13-item Beck Depression Inventory (BDI-score). The 13-item questionnaire assessing psychosomatic symptoms was used (PS-score). The 33 and 66 percentiles (tertiles) were formed on the basis of PS-score of the two groups separately. The highest PS-score percentile was compared with the combined first and second percentile. Higher PS-score implied impaired mental well-being especially in the unemployed but also in the control group. Insufficient social support and uncertainty about the future was associated with highest PS-score in the study group but not in the control group. High PS-score was associated with subjective mental problems in both groups. Impaired health and PS-score were associated in both groups. Our results suggest that unemployment is a powerful external stress factor and that psychosomatic symptoms were associated with impaired mental well-being.
The Sexual Abuse of Children: Cases Submitted to a Police Laboratory and the Scientific Evidence
Authors: Davies Anne 
Published: January 2017

This paper is based on a lecture given to an audience consisting mainly of social workers and paediatricians. The purpose of the talk was to explain the sort of evidence that could be provided by a forensic biologist in order to show that a child had been sexually assaulted, and to help identify the assailant. The introduction to the talk was composed of a review of the types of cases involving the sexual abuse of children that have been dealt with by this laboratory during the last two years (1984–85). A description was then given of the various biological materials which, if found in appropriate places, can substantiate an allegation of sexual assault. A brief reference was made to the persistence of semen in the vagina, rectum and mouth, and to the blood group substances which occur in different body fluids.
Suicide by Drowning in Uusimaa Province in Southern Finland
Authors: Auer A 
Published: January 2017

This study investigates drownings in Uusimaa province in Finland in order to form a picture of the people who end their lives in this way. The material consisted of 285 successive drownings, which were subject to autopsy at the Helsinki University Department of Forensic Medicine between 1978 and 1986 and for whom diatom analysis was carried out. There were 51 definitive cases of suicide by drowning. For these, an analysis was made of age and sex distribution, alcohol and drugs, scene of the incident, significant diseases, social group, place of residence, information on suicide notes, previous suicide attempts, treatment for mental problems, depression preceding the suicide, talk of suicide and heavy use of alcohol. According to this material the typical Finnish drowning suicide is a man from 21 to 30 years old, who belongs to the lowest social group, is unmarried, and lives in Helsinki. He drowns sober during June in the shallow water off the coast of the Gulf of Finland, has previously attempted suicide, received treatment for mental problems, and has been depressed recently.
Policing Diversity — Managing Complaints against the Police
Authors: Kennison Peter C 
Published: January 2017

This study takes a critical perspective in examining public attitudes towards police stop-and-search powers and, more particularly, police misconduct. It shows how police accountability works through the formal and complex system of complaints against police. It shows a system designed to favour the police against the citizen. In the eyes of some citizens this has tended to reduce the legitimacy of the complaints process, which has led to its under use. Certain police practices and services appear to impact more on diverse sections of the public than it does on the white community. It shows how aberrant police behaviour exposes some of the sociological issues such as black over-representation in public dissatisfaction and complaint statistics. The research also highlights the hidden figure of police deviance and misconduct. This study acknowledges future changes in complaints management proposed by the Home Secretary, David Blunkett MP. However, these proposals do not appear to go far enough. The complaints process is beset with a number of significant problems which include inaccessibility, complication and inequality. The study suggests, as the way forward, a model of ‘good practice’ using a pragmatic approach, which is customer-focused and overcomes many of the problems that allow for easy access, simplification and informality. The principle of civil libertarian ideals prevails, satisfying the legal notion, ‘justice must not only be done but must be seen to be done’.