bluuebunny/crossref_metadata_2025_split huggingface dataset:
UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer
Authors: Gilani Rabia A. , Phadke Sameer , Bao Li Wei , Lachacz Eric J. , Dziubinski Michele L. , Brandvold Kristoffer R. , Steffey Michael E. , Kwarcinski Frank E. , Graveel Carrie R. , Kidwell Kelley M. , Merajver Sofia D. , Soellner Matthew B. 
Published: May 2016

Abstract
Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.
Experimental Design: We have analyzed the anti–triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts.
Results: We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.
Conclusions: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC. Clin Cancer Res; 22(20); 5087–96. ©2016 AACR.
Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22+ B-cell Non-Hodgkin Lymphoma
Authors: Ogura Michinori , Tobinai Kensei , Hatake Kiyohiko , Davies Andrew , Crump Michael , Ananthakrishnan Revathi , Ishibashi Taro , Paccagnella M. Luisa , Boni Joseph , Vandendries Erik , MacDonald David 
Published: May 2016

Abstract
Purpose: To evaluate the safety, preliminary efficacy, and pharmacokinetics of inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, in combination with the immunochemotherapeutic regimen, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL).
Experimental Design: In part 1 (n = 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozogamicin. Part 2 (n = 10) confirmed the safety and tolerability of the maximum tolerated dose (MTD), which required a dose-limiting toxicity rate of &lt;33% in cycle 1 and &lt;33% of patients discontinuing before cycle 3 due to treatment-related adverse events (AEs). Part 3 (n = 22) evaluated the preliminary efficacy of inotuzumab ozogamicin plus R-CVP.
Results: The MTD was determined to be standard-dose R-CVP plus inotuzumab ozogamicin 0.8 mg/m2. The most common treatment-related grade ≥3 AEs in the MTD cohort (n = 38) were hematologic: neutropenia (74%), thrombocytopenia (50%), lymphopenia (42%), and leukopenia (47%). Among the 48 patients treated in the study, 13 discontinued due to AEs, most commonly thrombocytopenia (n = 10). Overall, 13 patients died, including one death due to treatment-related pneumonia secondary to neutropenia. Among patients receiving the MTD (n = 38), the overall response rate (ORR) was 84% (n = 32), including 24% (n = 9) with complete response; the ORR was 100% for patients with indolent lymphoma (n = 27) and 57% for those with aggressive histology lymphoma (n = 21).
Conclusions: Inotuzumab ozogamicin at 0.8 mg/m2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with relapsed/refractory CD22+ B-cell NHL. The study is registered at ClinicalTrials.gov (NCT01055496). Clin Cancer Res; 22(19); 4807–16. ©2016 AACR.
Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E–Deficient Mice
Authors: Higashi Yusuke , Sukhanov Sergiy , Shai Shaw-Yung , Danchuk Svitlana , Tang Richard , Snarski Patricia , Li Zhaohui , Lobelle-Rich Patricia , Wang Meifang , Wang Derek , Yu Hong , Korthuis Ronald , Delafontaine Patrice 
Published: May 2016

Background—
We have previously shown that systemic infusion of insulin-like growth factor-1 (IGF-1) exerts anti-inflammatory and antioxidant effects and reduces atherosclerotic burden in apolipoprotein E (Apoe)–deficient mice. Monocytes/macrophages express high levels of IGF-1 receptor (IGF1R) and play a pivotal role in atherogenesis, but the potential effects of IGF-1 on their function are unknown.

Methods and Results—

To determine mechanisms whereby IGF-1 reduces atherosclerosis and to explore the potential involvement of monocytes/macrophages, we created monocyte/macrophage–specific IGF1R knockout (MΦ-IGF1R-KO) mice on an Apoe
−/−
background. We assessed atherosclerotic burden, plaque features of stability, and monocyte recruitment to atherosclerotic lesions. Phenotypic changes of IGF1R-deficient macrophages were investigated in culture. MΦ-IGF1R-KO significantly increased atherosclerotic lesion formation, as assessed by Oil Red O staining of en face aortas and aortic root cross-sections, and changed plaque composition to a less stable phenotype, characterized by increased macrophage and decreased α-smooth muscle actin–positive cell population, fibrous cap thinning, and decreased collagen content. Brachiocephalic artery lesions of MΦ-IGF1R-KO mice had histological features implying plaque vulnerability. Macrophages isolated from MΦ-IGF1R-KO mice showed enhanced proinflammatory responses on stimulation by interferon-γ and oxidized low-density lipoprotein and elevated antioxidant gene expression levels. Moreover, IGF1R-deficient macrophages had decreased expression of ABCA1 and ABCG1 and reduced lipid efflux.

Conclusions—
Our data indicate that macrophage IGF1R signaling suppresses macrophage and foam cell accumulation in lesions and reduces plaque vulnerability, providing a novel mechanism whereby IGF-1 exerts antiatherogenic effects.
Pre- and postoperative inspiratory muscle training in patients undergoing cardiac surgery: systematic review and meta-analysis
Authors: Gomes Neto Mansueto , Martinez Bruno P , Reis Helena FC , Carvalho Vitor O 
Published: May 2016

Objective: To determine the effects of pre- and postoperative inspiratory muscle training on length of postoperative hospital stay and pulmonary function in patients undergoing cardiac surgery. Design and methods: We conducted a systematic search using databases (MEDLINE, CINAHL, EMBASE, PEDro and the Cochrane) to find controlled trials evaluating the effects of pre- and postoperative inspiratory muscle training. Results: Eight studies fulfilled the inclusion criteria. Four were about preoperative inspiratory muscle training (416 patients), three about postoperative inspiratory muscle training (115 patients) and one study about pre- and postoperative inspiratory muscle training (43 patients). Preoperative inspiratory muscle training resulted in improvement in: Reduction in length of postoperative hospital stay of −2 days (95% CI −3.4, −0.7, N = 302), inspiratory pressure of 16.7 cm H2O (95% CI 13.8, 19.5, N = 386), forced expiratory volume in one second of 3% predicted (95% CI 0.1, 6, N = 140), forced vital capacity of 4.6% predicted (95% CI 1.9, 7.4, N = 140). Patients that received preoperative training had an inspiratory muscle training reduced risk of postoperative pulmonary complications, (RR = 0.6; 95% CI 0.5 to 0.8; P = 0.0004, N = 386). Postoperative inspiratory muscle training resulted in improvement in inspiratory pressure of 16.5 cm H2O (95% CI 4.9, 27.8, N = 115), and tidal volume of 185 ml (95% CI 19.7, 349.8, N = 85). Conclusion: Pre- and postoperative inspiratory muscle training showed to be a beneficial intervention in the treatment of patients undergoing cardiac surgery.
Performance difficulties, activity limitations and participation restrictions of adolescents with developmental coordination disorder (DCD)
Authors: O’Dea Áine , Connell Amanda 
Published: May 2016

Introduction Developmental coordination disorder (DCD), also known as dyspraxia is a well-recognised childhood health condition. The two terms are used interchangeably. The profile of this condition in adolescence is less well known. This study examined the performance difficulties, activity limitations and participation restrictions experience of adolescents aged 16–19 years with developmental coordination disorder and identified what health services are required and/or accessed by these individuals. Method Secondary analysis of service need and use data were analysed for 141 adolescents with a diagnosis of dyspraxia registered on an Irish national database. The experience of disability was analysed for 40 individuals who completed the optional measure of activity and participation section, including the World Health Organization Disability Assessment Schedule II. Results Adolescents experience cognitive rather than physical impairments evolving from executive functioning and social skills. These impact on participation restrictions in academic, vocational, recreation and family life areas. Adolescents required access to the specific health services of occupational therapy and psychology. The health service needs of these adolescents were not adequately met. Conclusion Adolescents with developmental coordination disorder present with a complex array of difficulties that require specific health services. Future research needs to examine effective interventions, so that health service provision and policy can reflect the needs of these individuals.
Activation of dura-sensitive trigeminal neurons and increased c-Fos protein induced by morphine withdrawal in the rostral ventromedial medulla
Authors: Hitomi Suzuro , Kross Konrad , Kurose Masayuki , Porreca Frank , Meng Ian D 
Published: May 2016

AimsOveruse of medications used to treat migraine headache can increase the frequency of headaches. Sudden abstinence from migraine medication can also lead to a period of withdrawal-induced headaches. The aim of this study was to examine the effect of morphine withdrawal localized to the rostral ventromedial medulla (RVM) on the activity of dura-sensitive spinal trigeminal nucleus caudalis (Vc) neurons.MethodsRats were implanted with either morphine or placebo pellets for six to seven days before the microinjection of naloxone methiodide or phosphate-buffered saline into the RVM in urethane-anesthetized animals. Dura-sensitive neurons were recorded in the Vc and the production of c-Fos-like immunoreactivity was quantified.ResultsIn chronic morphine-treated animals, naloxone methiodide microinjections produced a significant increase both in ongoing and facial heat-evoked activity and an increase in Fos-positive neurons in the Vc and in the nucleus reticularis dorsalis, a brainstem region involved in diffuse noxious inhibitory controls.ConclusionsThese results indicate that activation of pronociceptive neurons in the RVM under conditions of morphine withdrawal can increase the activity of neurons that transmit headache pain. Modulation of the subnucleus reticularis dorsalis by the RVM may explain the attenuation of conditioned pain modulation in patients with chronic headache.
Delayed Anterior Cruciate Ligament Reconstruction in Young Patients With Previous Anterior Tibial Spine Fractures
Authors: Mitchell Justin J. , Mayo Meredith H. , Axibal Derek P. , Kasch Anthony R. , Fader Ryan R. , Chadayammuri Vivek , Terhune E. Bailey , Georgopoulos Gaia , Rhodes Jason T. , Vidal Armando F. 
Published: May 2016

Background: Avulsion fractures of the anterior tibial spine in young athletes are injuries similar to anterior cruciate ligament (ACL) injuries in adults. Sparse data exist on the association between anterior tibial spine fractures (ATSFs) and later ligamentous laxity or injuries leading to ACL reconstruction. Purpose: To better delineate the incidence of delayed instability or ACL ruptures requiring delayed ACL reconstruction in young patients with prior fractures of the tibial eminence. Study Design: Case series; Level of evidence, 4. Methods: We identified 101 patients between January 1993 and January 2012 who sustained an ATSF and who met inclusion criteria for this study. All patients had been followed for at least 2 years after the initial injury and were included for analysis after completion of a questionnaire via direct contact, mail, and/or telephone. If patients underwent further surgical intervention and/or underwent later ACL reconstruction, clinical records and operative reports pertaining to these secondary interventions were obtained and reviewed. Differences between categorical variables were assessed using the Fisher exact test. The association between time to revision ACL surgery and fracture type was assessed by Kaplan-Meier plots. The association between need for revision ACL surgery and age, sex, and mechanism of surgery was assessed using logistic regression. Results: Nineteen percent of all patients evaluated underwent delayed ACL reconstruction after a previous tibial spine fracture on the ipsilateral side. While there were a higher proportion of ACL reconstructions in type II fractures, there was not a statistically significant difference in the number of patients within each fracture group who went on to undergo later surgery ( P = .29). Further, there was not a significant association between fracture type, sex, or mechanism of injury as it related to the progression to later ACL reconstruction. However, there was a significant association between age at the time of injury and progression to later ACL reconstruction ( P = .02). For every year increase in age at the time of injury, the odds of going on to undergo delayed ACL reconstruction were greater by a factor of 1.3 (95% CI, 1.1-1.6). Conclusion: Although an ATSF is a relatively rare injury, our cohort of patients suggests that a subset of young patients with all types of tibial spine fractures will require later ACL reconstruction. There is a need to counsel patients that a delayed ACL rupture is a potential risk after an ATSF, especially as children approach skeletal maturity. Further patient follow-up and prospective studies are required.
Learning to Embody Leadership Through Mindfulness and Somatics Practice
Authors: Brendel William , Bennett Carmela 
Published: May 2016

The Problem Given the unpredictable nature of organizational life, leadership development programs that rely primarily on cognitive processing and critical reflection are no longer sufficient. What is required is an integrated pedagogy that enables individuals to access and embody a “way of being,” an aligned presence and purpose that spans all contexts so that the individual and leader are not separate entities but rather a fully cohesive self. To develop this capacity, reputable organizations are experimenting with holistic learning methodologies, including mindfulness and somatics practices. However, these methodologies have yet to be fully grounded in adult learning and leadership best practices, empirical research, mind–body principles, and leadership performance. The Solution Through a critical review of relevant theory, practice, and empirical research, this article conceptualizes a constructive developmental learning methodology, which integrates mindfulness and somatics practices that transform a leader’s relationship with behavior from the automatic to the consciously chosen realm. The article presents a practical model of embodied leadership where individuals learn ways to deepen awareness to include both the mind and body as an interdependent system to remain open, grounded, and engaged in a way that builds resilience, and resourcefulness, and improves relationships in complex environments. The Stakeholders Human resource development professionals, executive coaches, and aspiring leaders seek a holistic and practical leadership development approach, which is conceptually and empirically linked to leadership and organizational performance.
Brief Communication: Featured Article: Histone H2A mono-ubiquitination and cellular transformation are inversely related in N-nitrosodiethylamine-induced hepatocellular carcinoma
Authors: Bhattacharya Saikat , Reddy Divya , Ingle Arvind , Khade Bharat , Gupta Sanjay 
Published: May 2016

Aberrant changes in histone post-translational modifications are encountered frequently in diseases like cancer. Although histone H3 post-translational modifications have been extensively studied in context of diseases, the functionally important histone H2A PTM H2A119ub (H2Aub) has not gained much attention. In this study, we report that H2Aub markedly decreases in hepatocellular carcinoma. Usp21, a H2A deubiquitinase, is probably responsible for decrease in H2Aub. In addition, the H2Aub levels showed an inverse correlation with H3S10 phosphorylation (H3S10p) and the proliferative state of the cells. Downregulation of H2Aub is also associated with increased expression of growth factor gene lipocalin 2. Interestingly, we show that treatment of cells with histone deacetylase inhibitor trichostatin A results in increase of H2Aub and decrease in H3S10p. Our work for the first time suggests the in vivo association of H3S10p, H4ac, and H2A119ub with cellular transformation.
Adding the patient’s voice to our understanding of collaborative goal setting: How do patients with diabetes define collaborative goal setting?
Authors: Morris Heather L , Carlyle Kellie E , Elston Lafata Jennifer 
Published: May 2016

Background Patient reports of collaborative goal setting have repeatedly been associated with improved health outcomes, and the American Diabetes Association specifically encourages collaborative goal setting as a component of high quality care. Current limitations in our understanding of what needs to transpire for patients to denote goal setting as “collaborative”, remain a barrier to fostering collaborative goal setting in practice. Methods Four focus groups were conducted among 19 patients with diabetes. A semi-structured focus group guide was used to explore patient perceptions of collaborative goal setting and what needed to happen for goals to be considered collaboratively set. Focus group transcripts were coded using thematic analysis. Results Collaborative goal setting was described by patients as occurring within the context of a caring relationship where patients and health care providers: (1) listen and learn from each other; (2) share ideas; (3) agree on a measurable objective; and (4) support goal achievement. Patients also articulated clear responsibilities for themselves and clinicians and described collaborative goal setting as a process that occurs over time. Conclusions Patients perceived collaborative goal setting as a multidimensional process that occurs over time within the context of a caring relationship and encompasses distinct patient and clinician responsibilities.
Implementation of evidence-based medicine in a health promotion teaching block for Thai medical students
Authors: Liabsuetrakul Tippawan , Suntharasaj Thitima , Sangsupawanich Pasuree , Kongkamol Chanon , Pornsawat Panumad 
Published: May 2016

Background: Evidence-based medicine (EBM) is well known in medical practice. Although health promotion (HP) is promoted worldwide, there is still some debate as to whether EBM is needed or useful in the teaching of health promotion. Objective: To assess the perceived usefulness of EBM in the teaching of HP among medical students and faculty members. Methods: A comparative study was conducted between two groups of fourth-year medical students in the academic year 2012 during the five-week Health Promotion Teaching Block at Prince of Songkla University, southern Thailand. A one-week EBM course was conducted with half the students in the first week of the block and the other half of the students in the last week of the block. All activities in the HP block were similar except for the different periods of the one-week of EBM teaching. The effect on knowledge, ability and perceived application of EBM in future practice was assessed by student self-evaluations before versus after taking the EBM course, and by faculty member evaluation of the students’ end-of-block presentations. All evaluation items were rated from 1 (lowest) to 5 (highest). Data were analyzed using a t-test or Wilcoxon test, as appropriate. Results: The students’ self-evaluations of knowledge and ability on EBM between the two groups were similar. The perception that teaching EBM is beneficial in health promotion and future practice increased significantly ( p<0.001) in both groups. Faculty members rated higher scores for the first group than the second group, although the rating differences were not at the level of significance. Ninety percent of the students believed that EBM was a useful addition to the teaching of HP. Conclusions: Medical students and faculty members perceived that EBM is useful in the HP context. Future studies to evaluate the effect of using evidence-based teaching for health promotion are needed.
Olig2 is expressed late in human eosinophil development and controls Siglec-8 expression
Authors: Hwang Sae Mi , Uhm Tae Gi , Lee Seol Kyung , Kong Su-Kang , Jung Kyung Hwa , Binas Bert , Chai Young Gyu , Park Sung Woo , Chung Il Yup 
Published: May 2016

Abstract
Oligodendrocyte transcription factor 2, a basic helix–loop–helix transcription factor that binds to E-box motifs, is known to have a key role in determining lineage specification of oligodendrocytes and motor neurons. In the present study, we report that oligodendrocyte transcription factor 2 is expressed in human eosinophils and involved in transcriptional activation of the gene encoding sialic acid binding immunoglobulin-like lectin 8 (Siglec-8), a late eosinophil-differentiation marker known to exert eosinophil apoptosis. When cord blood CD34+ hematopoietic stem cells differentiated toward eosinophils during a 24-d culture period, oligodendrocyte transcription factor 2 protein was expressed in cord blood eosinophils on d 24, a time when cord blood eosinophils are considered fully differentiated, whereas it was not detectable on d 18 or at earlier time points. Oligodendrocyte transcription factor 2 protein was also abundantly expressed in human peripheral-blood eosinophils but not in neutrophils, monocytes, lymphocytes, or cord blood mast cells. RNA sequencing analysis showed that numerous genes, especially those encoding eosinophil surface molecules, were highly up-regulated along with OLIG2. Among the genes examined, SIGLEC-8 messenger RNA and protein were markedly down-regulated in parallel with OLIG2 by an oligodendrocyte transcription factor 2 small interfering RNA or a short hairpin RNA, as evidenced by real-time polymerase chain reaction, fluorescence-activated cell sorting, and Western blot analyses. In reporter gene and chromatin immunoprecipitation experiments, an E-box in the first intron was found to stimulate SIGLEC-8 gene transcription and to bind oligodendrocyte transcription factor 2. Hence, at least one important aspect of eosinophil differentiation is regulated by oligodendrocyte transcription factor 2, a transcription factor that has not previously been reported, to our knowledge, in normal granulocytes.