bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering the Molecular Secrets of Inflammatory Breast Cancer Biology: An Integrated Analysis of Three Distinct Affymetrix Gene Expression Datasets
Authors: Van Laere Steven J. , Ueno Naoto T. , Finetti Pascal , Vermeulen Peter , Lucci Anthony , Robertson Fredika M. , Marsan Melike , Iwamoto Takayuki , Krishnamurthy Savitri , Masuda Hiroko , van Dam Peter , Woodward Wendy A. , Viens Patrice , Cristofanilli Massimo , Birnbaum Daniel , Dirix Luc , Reuben James M. , Bertucci François 
Published: February 2013

Abstract
Background: Inflammatory breast cancer (IBC) is a poorly characterized form of breast cancer. So far, the results of expression profiling in IBC are inconclusive due to various reasons including limited sample size. Here, we present the integration of three Affymetrix expression datasets collected through the World IBC Consortium allowing us to interrogate the molecular profile of IBC using the largest series of IBC samples ever reported.
Experimental Design: Affymetrix profiles (HGU133-series) from 137 patients with IBC and 252 patients with non-IBC (nIBC) were analyzed using unsupervised and supervised techniques. Samples were classified according to the molecular subtypes using the PAM50-algorithm. Regression models were used to delineate IBC-specific and molecular subtype-independent changes in gene expression, pathway, and transcription factor activation.
Results: Four robust IBC-sample clusters were identified, associated with the different molecular subtypes (P &lt; 0.001), all of which were identified in IBC with a similar prevalence as in nIBC, except for the luminal A subtype (19% vs. 42%; P &lt; 0.001) and the HER2-enriched subtype (22% vs. 9%; P &lt; 0.001). Supervised analysis identified and validated an IBC-specific, molecular subtype-independent 79-gene signature, which held independent prognostic value in a series of 871 nIBCs. Functional analysis revealed attenuated TGF-β signaling in IBC.
Conclusion: We show that IBC is transcriptionally heterogeneous and that all molecular subtypes described in nIBC are detectable in IBC, albeit with a different frequency. The molecular profile of IBC, bearing molecular traits of aggressive breast tumor biology, shows attenuation of TGF-β signaling, potentially explaining the metastatic potential of IBC tumor cells in an unexpected manner. Clin Cancer Res; 19(17); 4685–96. ©2013 AACR.
Inhibition of HSP90 with AUY922 Induces Synergy in HER2-Amplified Trastuzumab-Resistant Breast and Gastric Cancer
Authors: Wainberg Zev A. , Anghel Adrian , Rogers Amy M. , Desai Amrita J. , Kalous Ondrej , Conklin Dylan , Ayala Raul , O'Brien Neil A. , Quadt Cornelia , Akimov Mikhail , Slamon Dennis J. , Finn Richard S. 
Published: February 2013

Abstract
HSP90 enables the activation of many client proteins of which the most clinically validated is HER2. NVP-AUY922, a potent HSP90 inhibitor, is currently in phase II clinical trials. To explore its potential clinical use in HER2-amplified breast and gastric cancers, we evaluated the effect of AUY922 alone and in combination with trastuzumab in both trastuzumab-sensitive and -resistant models. A panel of 16 human gastric and 45 breast cancer cell lines, including 16 HER2-amplified (3 and 13, respectively) cells, was treated with AUY922 over various concentrations. In both breast and gastric cancer, we used cell lines and xenograft models with conditioned trastuzumab-resistance to investigate the efficacy of AUY922 alongside trastuzumab. Effects of this combination on downstream markers were analyzed via Western blot analysis. AUY922 exhibited potent antiproliferative activity in the low nanomolar range (&lt;40 nmol/L) for 59 of 61 cell lines. In both histologies, HER2-amplified cells expressed greater sensitivity to AUY than HER2-negative cells. In conditioned trastuzumab-resistant models, AUY922 showed a synergistic effect with trastuzumab. In vitro, the combination induced greater decreases in HER2, a G2 cell-cycle arrest, and increased apoptosis. In a trastuzumab-resistant gastric cancer xenograft model, the combination of AUY922 and trastuzumab showed greater antitumor efficacy than either drug alone. These data suggest that AUY922 in combination with trastuzumab has unique efficacy in trastuzumab-resistant models. The combination of HSP90 inhibition and direct HER2 blockade represents a novel approach to the treatment of HER2-amplified cancers and clinical trials based on the above data are ongoing. Mol Cancer Ther; 12(4); 509–19. ©2013 AACR.
GX15-070 (Obatoclax) Induces Apoptosis and Inhibits Cathepsin D- and L–Mediated Autophagosomal Lysis in Antiestrogen-Resistant Breast Cancer Cells
Authors: Schwartz-Roberts Jessica L. , Shajahan Ayesha N. , Cook Katherine L. , Wärri Anni , Abu-Asab Mones , Clarke Robert 
Published: February 2013

AbstractIn estrogen receptor–positive (ER+) breast cancer cells, BCL2 overexpression contributes to antiestrogen resistance. Direct targeting of the antiapoptotic BCL2 members with GX15-070 (obatoclax), a BH3-mimetic currently in clinical development, is an attractive strategy to overcome antiestrogen resistance in some breast cancers. Recently, GX15-070 has been shown to induce both apoptosis and autophagy, yet the underlying cell death mechanisms have yet to be elucidated. Here, we show that GX15-070 is more effective in reducing the cell density of antiestrogen-resistant breast cancer cells versus sensitive cells and that this increased sensitivity of resistant cells to GX15-070 correlates with an accumulation of autophagic vacuoles. Formation of autophagosomes in GX15-070-treated cells was verified by changes in expression of the lipidation of microtubule-associated protein-1 light chain-3 and both confocal and transmission electron microscopy. While GX15-070 treatment promotes autophagic vacuole and autolysosome formation, p62/SQSTM1, a marker for autophagic degradation, levels accumulate. Moreover, GX15-070 exposure leads to a reduction in cathepsin D (CTSD) and L (CTSL1) protein expression that would otherwise digest autolysosome cargo. Thus, GX15-070 has dual roles in promoting cell death: (i) directly inhibiting antiapoptotic BCL2 family members, thereby inducing apoptosis; and (ii) inhibiting downstream CTSD and CTSL1 protein expression to limit the ability of cells to use degraded material to fuel cellular metabolism and restore homeostasis. Our data highlight a new mechanism of GX15-070-induced cell death that could be used to design novel therapeutic interventions for antiestrogen resistant breast cancer. Mol Cancer Ther; 12(4); 448–59. ©2013 AACR.
Bidirectional Regulation of Nuclear Factor-κB and Mammalian Target of Rapamycin Signaling Functionally Links Bnip3 Gene Repression and Cell Survival of Ventricular Myocytes
Authors: Dhingra Rimpy , Gang Hongying , Wang Yan , Biala Agnieszka K. , Aviv Yaron , Margulets Victoria , Tee Andrew , Kirshenbaum Lorrie A. 
Published: February 2013

Background—
Tumor necrosis factor-α and other proinflammatory cytokines activate the canonical Nuclear Factor (NF)-κB pathway through the kinase IKKβ. Previously, we established that IKKβ is also critical for Akt-mediated NF-κB activation in ventricular myocytes. Akt activates the kinase mammalian target of rapamycin (mTOR), which mediates important processes such as cardiac hypertrophy. However, whether mTOR regulates cardiac myocyte cell survival is unknown.

Methods and Results—
Herein, we demonstrate bidirectional regulation between NF-κB signaling and mTOR, the balance which determines ventricular myocyte survival. Overexpression of IKKβ resulted in mTOR activation and conversely overexpression of mTOR lead to NF-κB activation. Loss of function approaches demonstrated that endogenous levels of IKKβ and mTOR also signal through this pathway. NF-κB activation by mTOR was mediated by phosphorylation of the NF-κB p65 subunit increasing p65 nuclear translocation and activation of gene transcription. This circuit was also important for NF-κB activation by the canonical tumor necrosis factor-α pathway. Our previous work has shown that NF-κB signaling suppresses transcription of the death gene Bnip3 resulting in ventricular myocyte survival. Inhibition of mTOR with rapamycin decreased NF-κB activation resulting in increased Bnip3 expression and cell death. Conversely, mTOR overexpression suppressed Bnip3 levels and cell death of ventricular myocytes in response to hypoxia.

Conclusions—
To our knowledge, these data provide the first evidence for a bidirectional link between NF-κB signaling and mTOR that is critical in the regulation of Bnip3 expression and cardiac myocyte death. Hence, modulation of this axis may be cardioprotective during ischemia.
Prognostic Value of Changes in Galectin-3 Levels Over Time in Patients With Heart Failure
Authors: van der Velde A. Rogier , Gullestad Lars , Ueland Thor , Aukrust Pål , Guo Yu , Adourian Aram , Muntendam Pieter , van Veldhuisen Dirk J. , de Boer Rudolf A. 
Published: February 2013

Background—
In several cross-sectional analyses, circulating baseline levels of galectin-3, a protein involved in myocardial fibrosis and remodeling, have been associated with increased risk for morbidity and mortality in patients with heart failure (HF). The importance and clinical use of repeated measurements of galectin-3 have not yet been reported.

Methods and Results—

Plasma galectin-3 was measured at baseline and at 3 months in patients enrolled in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) trial (n=1329), and at baseline and at 6 months in patients enrolled in the Coordinating Study Evaluating Outcomes of Advising and Counseling Failure (COACH) trial (n=324). Patient results were analyzed by categorical and percentage changes in galectin-3 level. A threshold value of 17.8 ng/mL or 15% change from baseline was used to categorize patients. Increasing galectin-3 levels over time, from a low to high galectin-3 category, were associated with significantly more HF hospitalization and mortality compared with stable or decreasing galectin-3 levels (hazard ratio in CORONA, 1.60; 95% confidence interval, 1.13–2.25;
P
=0.007; hazard ratio in COACH, 2.38; 95% confidence interval, 1.02–5.55;
P
=0.046). In addition, patients whose galectin-3 increased by >15% between measurements had a 50% higher relative hazard of adverse event than those whose galectin-3 stayed within ±15% of the baseline value, independent of age, sex, diabetes mellitus, left ventricular ejection fraction, renal function, medication (β-blocker, angiotensin converting enzyme inhibitor, and angiotensin receptor blocker), and N-terminal probrain natriuretic peptide (hazard ratio in CORONA, 1.50; 95% confidence interval, 1.17–1.92;
P
=0.001). The impact of changing galectin-3 levels on other secondary end points was comparable.

Conclusions—
In 2 large cohorts of patients with chronic and acute decompensated HF, repeated measurements of galectin-3 level provided important and significant prognostic value in identifying patients with HF at elevated risk for subsequent HF morbidity and mortality.
Chronic Heart Failure Does Not Attenuate the Total Activity of Sympathetic Outflow to Skin During Whole-Body Heating
Authors: Cui Jian , Boehmer John P. , Blaha Cheryl , Lucking Robert , Kunselman Allen R. , Sinoway Lawrence I. 
Published: February 2013

Background—
Previous studies show that the rise in skin blood flow and cutaneous vascular conductance during heat stress is substantially attenuated in chronic heart failure (CHF) patients. The mechanisms responsible for this finding are not clear. In particular, little is known regarding the responses of skin sympathetic nerve activity (SSNA) that control the skin blood flow during heat stress in CHF patients. We examined the effects of a modest heat stress to test the hypothesis that SSNA responses could be attenuated in CHF.

Methods and Results—

We assessed SSNA (microneurography) from the peroneal nerve and skin blood flow (forearm laser Doppler) in 9 patients with stable class II–III CHF and in matched healthy subjects during passive whole-body heating with a water-perfused suit. Whole-body heating induced similar increases in internal temperature (≈0.6°C) in both groups. Whole-body heat stress evoked similar SSNA activation in CHF patients (Δ891±110 U/min) and the control subjects (Δ787±84 U/min;
P
=0.66), whereas the elevation in forearm cutaneous vascular conductance in patients with CHF was significantly lower than that in healthy control subjects (Δ131±29% vs Δ623±131%;
P
=0.001).

Conclusions—
The present data show that SSNA activation during a modest whole-body heat stress is not attenuated in CHF. Thus, the attenuated skin vasodilator response in CHF patients is not attributable to a reduction in total activity of sympathetic outflow to skin.
Pity the Women and Children: Punishment by Siege in Josephus’s Jewish War
Authors: Reeder Caryn A. 
Published: February 2013

Abstract
This paper analyzes the neglected theme of suffering women and children in Josephus’s Jewish War. Women and children did suffer the effects of sieges in Greco-Roman antiquity, but historiographers also use the stories of their suffering to interpret warfare. Josephus participates in this tradition by using the imagery of suffering women and children to condemn the Jewish rebels, a presentation which is also influenced by Deut 28 and Lamentations. The warnings against rebellion in J.W. 2.237, 400, and 5.418 heighten the rhetorical power of this condemnation by offering the alternative of surrender for the sake of women and children.
Living Organ Donation and Minors: A Major Dilemma
Authors: Broeckx Nils 
Published: February 2013

Abstract
In this article, the case of living organ donation by minors is discussed. A distinction can be made between minors who are in fact already competent and those who are not. Minors who are in fact competent, should be able to decide on organ donation under the same conditions as competent adults. Incompetent minors could be allowed to act as living organ donors under exceptional circumstances on the basis of a best interest test. Decisions on living organ donation by incompetent minors should be embedded into a procedural framework in which parental consent, the approval of an independent body of health professionals, and the minor’s wishes play a substantial role.
The enduring mental health impact of mass violence: A community comparison study of Cambodian civilians living in Cambodia and Thailand
Authors: Mollica Richard F , Brooks Robert , Tor Svang , Lopes-Cardozo Barbara , Silove Derrick 
Published: February 2013

Background: No population-based studies have directly compared the long-term health and mental health outcomes of conflict- versus non-conflict-affected communities from the same ethnic background. Aims: To identify and compare levels of psychiatric morbidity between a traumatized and non-traumatized civilian community; to investigate the long-term impact of mass violence. Methods: Double-stratified community surveys in Siem Reap and Surin provinces were conducted by highly qualified Cambodian interviewers using culturally validated survey instruments with known psychometric properties. These included Cambodian versions of the Hopkins Symptom Checklist-25, the Harvard Trauma Questionnaire and the Medical Outcome Study Short Form. Results: Siem Reap and Surin respondents experienced 12,266 and 621 major trauma events, respectively; 745 (76.2%) Siem Reap respondents and six (0.6%) Surin respondents reported torture events; 499 (49.5%) Siem Reap respondents and 203 (19.7%) Surin respondents met the clinical threshold for depression (OR 4.01, 95% CI 3.29–4.88); 204 (20.6%) Siem Reap respondents and 23 (2.2%) Surin respondents met the clinical threshold for post-traumatic stress disorder (PTSD) (OR 11.39, 95% CI 7.3–17.7). The MOS physical disability was higher in Siem Reap versus Surin respondents (74 (7.5%) vs 13 (1.3%), χ2 = 47.4 df = 1, p < .001). Health status was poorest among Siem Reap respondents when compared with Surin respondents (mean score 1.59 vs 0.59, respectively; t = 19.85 df = 2018, p < .001). Path analysis reveals that recent and past extreme violence are associated with the health and mental health status of the Siem Reap community. Conclusion: After 25 years, the Khmer civilian population that experienced the Pol Pot genocide continues to suffer psychiatric morbidity and poor health.
Psychometric evaluation of the Dutch version of the Mental Health Recovery Measure (MHRM)
Authors: van Nieuwenhuizen Chijs , Wilrycx Greet , Moradi Mozhgan , Brouwers Evelien 
Published: February 2013

Background: During the past decade, the mental health consumer movement has drawn the attention of mental health providers, researchers and policy makers to the concept of recovery. Traditionally, recovery primarily refers to the remission of symptoms. Nowadays, recovery is also regarded in a sense that all individuals, even those with severe psychiatric disabilities, can improve. Accordingly, recovery for people with severe mental illness refers to hope and optimism, empowerment, regained control and increased self-esteem, illness self-management and engagement in meaningful daily activities (Corrigan, Giffort, Rashid, Leary & Okeke, 1999; Jacobson & Greenley, 2001; Leamy, Bird, le Boutillier, Williams & Slade, 2011; van Gestel-Timmermans, Brouwers, van Assen, Bongers & van Nieuwenhuizen, 2012). Little empirical research, however, has been done and instruments to measure recovery are scarce. Aims: In the current study, the psychometric properties of the Dutch version of the Mental Health Recovery Measure (MHRM) are explored. Convergent and divergent validity of the MHRM was assessed using standardized measures of hope (Hope Herth Index (HHI)), recovery-promoting professional competence (Recovery Promoting Relationships Scale (RPRS)) and general physical health and well-being (RAND Measure of Health-Related Quality of Life (RAND-36)). Methods: A factor analysis was conducted and Cronbach’s α of the MHRM scales was assessed. The construct validity was assessed by computing the intercorrelations of the MHRM, HHI, RPRS and RAND-36. Results: Data were available for 212 patients: 70 patients completed the MHRM, HHI and RAND 36 and 142 filled out the MHRM and RPRS. Exploratory factor analysis resulted in an interpretable three-factor solution. Cronbach’s α ranged from 0.86 to 0.94. The convergent validity of the instrument was satisfactory; the divergent validity was less clear. Conclusions: This study offers evidence to suggest that the Dutch version of the MHRM is a reliable measure (in terms of internal consistency) with a generally acceptable convergent and divergent validity. Further research is needed to clarify the extent to which the MHRM is sensitive enough to capture the individual recovery process of patients.
A Profile of Self-Care Behaviors in Emerging Adults With Type 1 Diabetes
Authors: Hendricks Melissa , Monaghan Maureen , Soutor Sari , Chen Rusan , Holmes Clarissa S. 
Published: February 2013

Purpose The purpose of this study is to characterize daily diabetes self-care behaviors and to evaluate associations among self-care behaviors, psychosocial adjustment, and glycemic control in an understudied sample of emerging adults with type 1 diabetes. Methods Forty-nine emerging adults (65% women; ages 18-26 years) completed 2 diabetes interviews to assess self-care behaviors and self-report measures of psychosocial adjustment. Glycemic control was assessed via hemoglobin A1C. Results Diabetes self-care behaviors varied widely and were largely suboptimal; only a small percentage of participants demonstrated self-care behaviors consistent with national and international recommendations. Psychosocial adjustment was within normal limits and was unrelated to frequency of self-care behaviors in this sample. Mean glycemic control (8.3%) was higher than the recommended A1C level (< 7.0%) for this age group. Use of intensive (eg, multiple daily injections or pump) insulin regimens was related to better glycemic control. Conclusions The majority of emerging adults in this sample did not engage in optimal daily diabetes self-care. Intensive insulin therapy was associated with better glycemic control without corresponding psychosocial distress. Diabetes care behaviors could be improved in this age group, and emerging adults may benefit from targeted education and behavioral support to enhance diabetes self-management and optimize health outcomes.
Comprehensive Management of Presbycusis: Central and Peripheral
Authors: Parham Kourosh , Lin Frank R. , Coelho Daniel H. , Sataloff Robert T. , Gates George A. 
Published: February 2013

The prevailing otolaryngologic approach to treatment of age‐related hearing loss (ARHL), presbycusis, emphasizes compensation of peripheral functional deficits (ie, hearing aids and cochlear implants). This approach does not address adequately the needs of the geriatric population, 1 in 5 of whom is expected to consist of the “old old” in the coming decades. Aging affects both the peripheral and central auditory systems, and disorders of executive function become more prevalent with advancing age. Growing evidence supports an association between age‐related hearing loss and cognitive decline. Thus, to facilitate optimal functional capacity in our geriatric patients, a more comprehensive management strategy of ARHL is needed. Diagnostic evaluation should go beyond standard audiometric testing and include measures of central auditory function, including dichotic tasks and speech‐in‐noise testing. Treatment should include not only appropriate means of peripheral compensation but also auditory rehabilitative training and counseling.
Consistency of Voice Frequency and Perturbation Measures in Children
Authors: Hill Courtney A. , Ojha Shilpa , Maturo Stephen , Maurer Rie , Bunting Glenn , Hartnick Christopher J. 
Published: February 2013

ObjectiveEvaluate normal pediatric voice frequency and perturbation measures with Voice Evaluation Suite (VES) and Multi Dimensional Voice Program (MDVP), determine the consistency of these measures over time, and understand which measures might be most useful for evaluating children with voice disorders.Study DesignProspective, longitudinal study of normal voices of 50 children aged 4 to 17 years.SettingPediatric otolaryngology clinic within tertiary hospital.Subjects and MethodsTwo tests of sustained utterances from each child were evaluated by 2 computerized voice analysis programs for frequency and perturbation. Intraclass correlation coefficient (ICC) was used to assess the reliability between the samples.ResultsChildren (male/female, 1.08:1) with a mean age of 8.34 years were tested on an average of 54.2 minutes apart. Each test included 4 utterances; 1 was analyzed by MDVP, and 3 grouped utterances were averaged and evaluated by VES. Fundamental frequency had excellent reliability (ICC = 0.95) in both VES and MDVP. Jitter, shimmer, and noise to harmonic ratio were poorly reliable (ICC ≤0.4) in MDVP but had good to excellent reliability (ICC 0.66‐0.8) in VES.ConclusionSingle, sustained utterances in children provide consistent measures of frequency. Perturbation is not reliably measured by such testing, but averaging multiple samples yields improved consistency. Evaluating acoustic measure stability in spontaneous speech and in sustained utterances cued by a tuning frequency can provide further insight on pediatric voice consistency.