bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Therapy of VEGFR2 and EGFR Significantly Inhibits Growth of Anaplastic Thyroid Cancer in an Orthotopic Murine Model
Authors: Gule Maria K. , Chen Yunyun , Sano Daisuke , Frederick Mitchell J. , Zhou Ge , Zhao Mei , Milas Zvonimir L. , Galer Chad E. , Henderson Ying C. , Jasser Samar A. , Schwartz David L. , Bankson James A. , Myers Jeffrey N. , Lai Stephen Y. 
Published: January 2011

AbstractPurpose: Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear.Experimental Design: Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature.Results: Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P &lt; 0.001) and 66.6% (P &lt; 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P &lt; 0.01) and vascular volume fraction (P &lt; 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control.Conclusion: The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo. Clin Cancer Res; 17(8); 2281–91. ©2011 AACR.
Blocking the NOTCH Pathway Inhibits Vascular Inflammation in Large-Vessel Vasculitis
Authors: Piggott Kisha , Deng Jiusheng , Warrington Kenneth , Younge Brian , Kubo Jessica T. , Desai Manisha , Goronzy Jörg J. , Weyand Cornelia M. 
Published: January 2011

Background—
Giant cell arteritis is a granulomatous vasculitis of the aorta and its branches that causes blindness, stroke, and aortic aneurysm. CD4 T cells are key pathogenic regulators, instructed by vessel wall dendritic cells to differentiate into vasculitic T cells. The unique pathways driving this dendritic cell–T-cell interaction are incompletely understood, but may provide novel therapeutic targets for a disease in which the only established therapy is long-term treatment with high doses of corticosteroids.

Methods and Results—
Immunohistochemical and gene expression analyses of giant cell arteritis-affected temporal arteries revealed abundant expression of the NOTCH receptor and its ligands, Jagged1 and Delta1. Cleavage of the NOTCH intracellular domain in wall-infiltrating T cells indicated ongoing NOTCH pathway activation in large-vessel vasculitis. NOTCH activation did not occur in small-vessel vasculitis affecting branches of the vasa vasorum tree. We devised 2 strategies to block NOTCH pathway activation: γ-secretase inhibitor treatment, preventing nuclear translocation of the NOTCH intracellular domain, and competing for receptor-ligand interactions through excess soluble ligand, Jagged1-Fc. In a humanized mouse model, NOTCH pathway disruption had strong immunosuppressive effects, inhibiting T-cell activation in the early and established phases of vascular inflammation. NOTCH inhibition was particularly effective in downregulating Th17 responses, but also markedly suppressed Th1 responses.

Conclusions—
Blocking NOTCH signaling depleted T cells from the vascular infiltrates, implicating NOTCH- NOTCH ligand interactions in regulating T-cell retention and survival in vessel wall inflammation. Modulating the NOTCH signaling cascade emerges as a promising new strategy for immunosuppressive therapy of large-vessel vasculitis.
Antihypertensive Treatment and Change in Blood Pressure Are Associated With the Progression of White Matter Lesion Volumes
Authors: Godin Ophélia , Tzourio Christophe , Maillard Pauline , Mazoyer Bernard , Dufouil Carole 
Published: January 2011

Background—
Blood pressure (BP) is recognized as a major risk factor for white matter lesions (WMLs), but longitudinal data are scarce, and there is insufficient evidence for the benefit of antihypertensive therapy on WML progression. We studied the relationship between BP change and WML volume progression over time in a sample of 1319 elderly individuals who had 2 cerebral magnetic resonance imaging examinations 4 years apart. We also examined the impact of antihypertensive treatment on WML progression.

Methods and Results—

Subjects were participants from the Three-City (3C)–Dijon Magnetic Resonance Imaging Study, a prospective population-based cohort of elderly ≥65 years of age. WML volumes and their progression were estimated with the use of a fully automatic procedure. We performed ANCOVA models first to assess the association between BP change and WML progression and second to estimate the relation between antihypertensive treatment and WML load progression. Baseline and change in BP were significant predictors of higher WML progression over time after controlling for potential confounders. Among subjects with high SBP (≥160 mm Hg) at baseline not treated by antihypertensive medication, antihypertensive treatment started within 2 years was related to a smaller increase in WML volume at a 4-year follow-up (0.24 cm
3
; SE=0.44 cm
3
) than no hypertensive treatment (1.60 cm
3
; SE=0.26 cm
3
;
P
=0.0008) on multivariable modeling.

Conclusions—
Our findings reinforce the hypothesis that hypertension is a strong predictor of WML and that adequate treatment may reduce the course of WML progression. Because WMLs are linked to both dementia and stroke risks, these results could have implications for future preventive trials.
Kissinger, China, Congress, and the Lost Chance for Cambodia
Authors: Connolly Chris 
Published: January 2011

AbstractHenry Kissinger has been persistent in his claim that the U.S. Congress's failure to adequately supply South Vietnam was the ultimate cause of its collapse in 1975 – a claim many historians dispute. An incident that has received less attention is the role of Congress in terminating a potential negotiated settlement of the civil war in Cambodia by imposing a halt of U.S. bombing there in the summer of 1973. This article demonstrates that in this case, Kissinger's claims are not without foundation. Although the conclusions are tentative without the full Chinese record, the evidence suggests that terminating U.S. military operations in Cambodia fatally undermined Chinese efforts to negotiate the removal of Lon Nol as Cambodian head of state and the establishment of a coalition government involving the Khmer Rouge but with Sihanouk at its head.
Awareness of Diabetes Risk Factors and Prevention Strategies Among a Sample of Low-Income Latinos With No Known Diagnosis of Diabetes
Authors: Rosal Milagros C. , Borg Amy , Bodenlos Jamie S. , Tellez Trinidad , Ockene Ira S. 
Published: January 2011

Purpose This study assessed awareness of type 2 diabetes risk and severity, perceived risk factors, knowledge of diabetes prevention strategies, and challenges of and opportunities for prevention among low-income Latinos in Lawrence, Massachusetts. Methods Qualitative research design. Latinos with no known diagnosis of diabetes participated in 4 focus groups, conducted in Spanish, which were recorded and transcribed for systematic analysis. Results The sample, (N = 41) was largely female (85%) with a wide age range (22-76 years), most (71%) had an educational level of high school or less, and less than half (46%) were employed. Participants had basic knowledge of diabetes, but gaps were apparent. Many perceived family history of diabetes, poor diet, emotional distress, and stress associated with the United States as risk factors for diabetes. There was little or no awareness of risk associated with Latino ethnicity, gestational diabetes, hypertension, lipid abnormalities, or obesity. Few cited physical activity or weight loss as diabetes prevention strategies. More than half the participants perceived themselves at low risk for diabetes. Conclusions This Latino sample had limited knowledge of diabetes risk factors and lifestyle changes that can prevent or delay diabetes onset. Insights for intervening for diabetes prevention are offered.
Chronic migraine: Classification and comparisons
Authors: Katsarava Z , Manack A , Yoon M-S , Obermann M , Becker H , Dommes P , Turkel C , Lipton RB , Diener HC 
Published: January 2011

Objective: The objective of our study was to field test different chronic migraine (CM) criteria and compare CM epidemiological profiles, which include demographic, personal, and lifestyle characteristics, with high-frequency episodic migraine (HFEM) and low-frequency episodic migraine (LFEM). Methods: Questionnaires were mailed to a random sample of 18,000 18–65-year-olds in demographically diverse regions of Germany. The epidemiological data for the three classifications of CM, LFEM and HFEM were assessed using descriptive statistics, Pearson Chi-square, and analysis of variance tests. Results: Among 9350 respondents, CM_I was the most restrictive ( N = 37, 0.4%), followed by CM_II ( N = 45, 0.5%) and CM_III ( N = 185, 2.0%). CM groups did not differ in distribution by age, gender, body mass index, education or smoking and alcohol consumption. Compared to those with LFEM and HFEM, those with CM (CM_III) had significantly different epidemiological profiles. Conclusions: CM prevalence varies by case definition. The epidemiological profiles of the three CM groups are similar but differ significantly from those of HFEM and LFEM. Optimal definitions for clinical practice and epidemiological research require additional field testing.
Headaches and sleep problems among adults in the United States: Findings from the National Comorbidity Survey–Replication Study
Authors: Lateef Tarannum , Swanson Sonja , Cui Lihong , Nelson Karin , Nakamura Erin , Merikangas Kathleen 
Published: January 2011

Background: Several studies have demonstrated an association between headache and disturbed sleep. None have examined this association across the headache spectrum. Our goal was to determine whether migraine and migraine with aura differ from nonmigraine headache in terms of associated insomnia complaints or severity of sleep problems. Methods: A probability sample of US adults was used. A structured interview administered by trained interviewers was used. Diagnostic criteria for migraine and migraine with aura were based on the International Headache Society classification. The presence or absence of four forms of sleep disturbance associated with an insomnia diagnosis was ascertained. Results: There was a significant association between frequent severe headache, including migraine with and without aura, and disordered sleep. Adults with headache reported more frequently difficulty initiating sleep (odds ratio [confidence interval] = 2.0 [1.6–2.5]), difficulty staying asleep (2.5 [2.1–3]), early morning awakening (2.0 [1.7–2.5]) and daytime fatigue (2.6 [2.2–3.2]) and also were more than twice as likely to report three or more of these symptoms(2.5 [2–3.1]) compared to the individuals without headache. Discussion: Adults with severe headache are at significantly higher risk of also suffering from sleep problems, when compared with the general population, regardless of specific headache type. Optimal treatment of headache must include investigation for sleep disorders and vice versa.
Influence of retirement and work stress on headache prevalence: A longitudinal modelling study from the GAZEL Cohort Study
Authors: Sjösten Noora , Nabi Hermann , Westerlund Hugo , Singh-Manoux Archana , Dartigues Jean-François , Goldberg Marcel , Zins Marie , Oksanen Tuula , Salo Paula , Pentti Jaana , Kivimäki Mika , Vahtera Jussi 
Published: January 2011

Aims: The aims of this study were to examine trajectories of headache in relation to retirement and to clarify the role of work stress and stress-prone personality. Methods: Headache prevalence during the 7 years before and after retirement was measured by annual questionnaires from GAZEL cohort comprising French national gas and electricity company employees ( n = 12,913). Odds ratios and 95% confidence intervals for headache during pre- peri- and post-retirement were calculated. The role of effect modifiers (work stress, type A or hostile personality) was tested by multiplicative interactions and synergy indices. Results: An 11–13% reduction in headache prevalence was found during pre- and post-retirement, whereas decline was much steeper (46%) during the retirement transition. In absolute terms, the decline was greater among persons with high work stress or stress-prone personality than among other participants. Conclusions: Retirement is associated with a decrease in headache prevalence, particularly among persons with a high amount of work stress or proneness to over-react to stress.
Effect of Calcium Phosphate–Hybridized Tendon Graft on Biomechanical Behavior in Anterior Cruciate Ligament Reconstruction in a Goat Model
Authors: Mutsuzaki Hirotaka , Sakane Masataka , Fujie Hiromichi , Hattori Shinya , Kobayashi Hisatoshi , Ochiai Naoyuki 
Published: January 2011

Background: The authors developed a novel technique to improve tendon-bone attachment by hybridizing calcium phosphate with a tendon graft using an alternate soaking process. However, the long-term result is unclear regarding the function of the anterior cruciate ligament–reconstructed knee and the interface between the tendon and the bone. Purpose: To clarify the effects of the calcium phosphate–hybridized tendon graft by analyzing the biomechanical behavior of the reconstructed knee, bone tunnel wall, and interface between the tendon and the bone, compared with the untreated knee at 1 year in goats. Study Design: Controlled laboratory study. Methods: The authors analyzed knee kinematics and in situ forces in a replacement graft, as well as computed tomography for new bone formation in the bone tunnel and histology of the tendon-bone interface, with and without the calcium phosphate–hybridized tendon graft. Results: In the calcium phosphate group, the anteroposterior translations in the reconstructed knees were shorter and the corresponding in situ forces greater than those in the control group at full extension and 60° of knee flexion. The in situ force in response to applied internal tibial torques in the calcium phosphate group at full extension was greater than that in the control group. More new bone formation in the bone tunnel and cartilage layer between the tendon-bone interface at the joint aperture site of the calcium phosphate group was observed than in the control group. Conclusion: The calcium phosphate–hybridized tendon graft promotes knee stability because of the firm tendon-bone healing with cartilage layer and new bone formation. Clinical Relevance: Anterior cruciate ligament reconstruction using the calcium phosphate–hybridized tendon graft may lead to good long-term outcomes.
Review Article: Persistent organic pollutants and landfills - a review of past experiences and future challenges
Authors: Weber Roland , Watson Alan , Forter Martin , Oliaei Fardin 
Published: January 2011

The landfilling and dumping of persistent organic pollutants (POPs) and other persistent hazardous compounds, such as polychlorinated biphenyls (PCBs), hexachlorocyclohaxane (HCH), polybrominated diphenylether (PBDEs) or perfluorooctane sulfonic acid (PFOS) can have significant adverse environmental consequences. This paper reviews past experiences with such disposal practices and highlights their unsustainability due to the risks of contamination of ecosystems, the food chain, together with ground and drinking water supplies. The use and associated disposal of POPs have been occurring for over 50 years. Concurrent with the phase-out of some of the most hazardous chemicals, the production of new POPs, such as brominated and fluorinated compounds has increased since the 1990s. These latter compounds are commonly used in a wide range of consumer goods, and as consumer products reach the end of their useful lives, ultimately enter waste recycling and disposal systems, in particular at municipal landfills. Because of their very slow, or lack of degradability, POPs will persist in landfills for many decades and possibly centuries. Over these extended time periods engineered landfill systems and their liners are likely to degrade, thus posing a contemporary and future risk of releasing large contaminant loads to the environment. This review highlights the necessity for alternative disposal methods for POP wastes, including destruction or complete removal from potential environmental release. In addition to such end of pipe solutions a policy change in the use pattern of persistent toxic chemicals is inevitable. In addition, inventories for the location and quantity of POPs in landfills, together with an assessment of their threat to ecosystems, drinking water and food resources are identified as key measures to facilitate appropriate management of risks. Finally the challenges of POP wastes in transition/developing countries, the risk of increased leaching of POPs from landfills due to climate change, and the possible negative impact of natural attenuation processes are considered.
Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy
Authors: Sandberg-Wollheim Magnhild , Alteri Enrica , Moraga Margaretha Stam , Kornmann Gabrielle 
Published: January 2011

Background: Women with multiple sclerosis (MS) are advised to discontinue interferon-beta therapy before trying to conceive. Unplanned pregnancies occur and risks related to exposure remain unclear. Methods: To determine pregnancy outcomes following interferon-beta therapy, we examined pregnancies from a global drug safety database containing individual case safety reports received in the post-marketing setting and safety data from clinical trials of subcutaneous interferon beta-1a in MS. Results: One thousand and twenty-two cases of exposure to subcutaneous interferon beta-1a during pregnancy were retrieved; 679 had a documented outcome. In cases for which exposure duration was available ( n = 231), mean time of foetal exposure to subcutaneous interferon beta-1a before treatment discontinuation was 28 days; most pregnancies (199/231; 86.1%) were exposed for ≤45 days. To avoid bias, only outcomes for prospective data ( n = 425) in pregnancies exposed to interferon beta-1a in utero were analysed further. Of these, 324 (76.2%) resulted in normal live births and four (0.9%) in live births with congenital anomalies (3 [0.7%] were ‘major’). Four (0.9%) pregnancies resulted in stillbirths (1 [0.2%] with foetal defects). There were 5 (1.2%) ectopic pregnancies, 49 (11.5%) spontaneous abortions and 39 (9.2%) elective terminations. Most pregnancies exposed to subcutaneous interferon beta-1a in utero were associated with normal live births. The rates of spontaneous abortion and major congenital anomalies in live births were in line with those observed in the general population. Conclusions: These data should be taken into account when considering options for women with MS who become pregnant or who are planning pregnancy while on treatment with subcutaneous interferon beta-1a.
Impact of exposure to interferon beta-1a on outcomes in patients with relapsing–remitting multiple sclerosis: exploratory analyses from the PRISMS long-term follow-up study
Authors: Uitdehaag Bernard , Constantinescu Cris , Cornelisse Peter , Jeffery Douglas , Kappos Ludwig , Li David , Sandberg-Wollheim Magnhild , Traboulsee Anthony , Verdun Elisabetta , Rivera Victor 
Published: January 2011

Objective: To explore the effects of exposure to subcutaneous (sc) interferon (IFN) beta-1a on efficacy in patients with relapsing–remitting multiple sclerosis (RRMS) enrolled in the PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study. Methods: Patients with RRMS received IFN beta-1a, 44 or 22 µg sc three times weekly (tiw), or placebo, for 2 years, at which point placebo recipients were re-randomized to IFN beta-1a, 44 or 22 µg sc tiw, for a further 2–4 years. Long-term follow-up visits occurred 7–8 years after enrolment and allowed participation of patients who had previously discontinued treatment. Post hoc descriptive analyses were conducted within the lower (MIN) and upper (MAX) quartiles of patients divided according to cumulative dose of IFN beta-1a and cumulative time on treatment. Outcomes were explored in patients initially randomized to IFN beta-1a, 44 µg sc tiw, who had received continuous or noncontinuous therapy during the study. Results: For both cumulative dose and time analyses, the MIN and MAX groups comprised 96 and 95 patients, respectively. The continuous and noncontinuous groups included 45 and 91 patients, respectively. The MAX DOSE and MAX TIME groups had lower annualized relapse rates, lower rates of conversion to secondary progressive MS, lower percentages of patients with Expanded Disability Status Scale progression, higher percentages of relapse-free patients, and less T2 burden of disease than the MIN groups. The continuous therapy group had a lower annualized relapse rate and lower percentages of patients with Expanded Disability Status Scale progression or conversion to secondary progressive MS than the noncontinuous therapy group. Conclusions: The findings of these post hoc analyses suggest that high exposure to sc IFN beta-1a may be associated with better clinical outcomes than low exposure, and also highlight the importance of maximizing adherence. Additional prospective investigation is warranted to evaluate further the effects of treatment exposure on outcomes and to determine the benefits of interventions to improve adherence.
High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia
Authors: Warsch Wolfgang , Kollmann Karoline , Eckelhart Eva , Fajmann Sabine , Cerny-Reiterer Sabine , Hölbl Andrea , Gleixner Karoline V. , Dworzak Michael , Mayerhofer Matthias , Hoermann Gregor , Herrmann Harald , Sillaber Christian , Egger Gerda , Valent Peter , Moriggl Richard , Sexl Veronika 
Published: January 2011

AbstractIn BCR-ABL1+ leukemia, drug resistance is often associated with up-regulation of BCR-ABL1 or multidrug transporters as well as BCR-ABL1 mutations. Here we show that the expression level of the transcription factor STAT5 is another parameter that determines the sensitivity of BCR-ABL1+ cells against tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, or dasatinib. Abelson-transformed cells, expressing high levels of STAT5, were found to be significantly less sensitive to TKI-induced apoptosis in vitro and in vivo but not to other cytotoxic drugs, such as hydroxyurea, interferon-β, or Aca-dC. The STAT5-mediated protection requires tyrosine phosphorylation of STAT5 independent of JAK2 and transcriptional activity. In support of this concept, under imatinib treatment and with disease progression, STAT5 mRNA and protein levels increased in patients with Ph+ chronic myeloid leukemia. Based on our data, we propose a model in which disease progression in BCR-ABL1+ leukemia leads to up-regulated STAT5 expression. This may be in part the result of clonal selection of cells with high STAT5 levels. STAT5 then accounts for the resistance against TKIs, thereby explaining the dose escalation frequently required in patients reaching accelerated phase. It also suggests that STAT5 may serve as an attractive target to overcome imatinib resistance in BCR-ABL1+ leukemia.