tbuckley/cabot-search huggingface dataset:
Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: a 6-month randomised controlled trial
Authors: Lisanne F ten Brinke, Niousha Bolandzadeh, Lindsay S Nagamatsu, Chun Liang Hsu, Jennifer C Davis, Karim Miran-Khan, Teresa Liu-Ambrose
Journal: British Journal of Sports Medicine (2014)

Background Mild cognitive impairment (MCI) is a well-recognised risk factor for dementia and represents a vital opportunity for intervening. Exercise is a promising strategy for combating cognitive decline by improving brain structure and function. Specifically, aerobic training (AT) improved spatial memory and hippocampal volume in healthy community-dwelling older adults. In older women with probable MCI, we previously demonstrated that resistance training (RT) and AT improved memory. In this secondary analysis, we investigated: (1) the effect of RT and AT on hippocampal volume and (2) the association between change in hippocampal volume and change in memory. Methods 86 women aged 70–80 years with probable MCI were randomly assigned to a 6-month, twice-weekly programme of: (1) AT, (2) RT or (3) balance and tone training (BAT; ie, control). At baseline and trial completion, participants performed a 3T MRI scan to determine hippocampal volume. Verbal memory and learning were assessed by Rey's Auditory Verbal Learning Test. Results Compared with the BAT group, AT significantly improved left, right and total hippocampal volumes (p≤0.03). After accounting for baseline cognitive function and experimental group, increased left hippocampal volume was independently associated with reduced verbal memory and learning performance as indexed by loss after interference (r=0.42, p=0.03). Conclusions Aerobic training significantly increased hippocampal volume in older women with probable MCI. More research is needed to ascertain the relevance of exercise-induced changes in hippocampal volume on memory performance in older adults with MCI. Trail registration number NCT00958867.
Implementing the European Respiratory Roadmap: halfway there?
Authors: Nadia Kamel
Journal: European Respiratory Journal (2014)

Soon 5 years will have passed since the European Respiratory Society (ERS) pronounced its 10-year vision for respiratory medicine with the launch of the European Respiratory Roadmap. With regards to research, the following was stated: "There is a great need to find new, effective ways for collaboration between academic research and innovators, in order to develop better medicines and improved diagnostic methods. A significant problem is the real deficiency of new innovative medicines in the respiratory field, as only nine new therapies have been developed over the past 40 years" [1]. We are swiftly approaching the halfway mark for the 10-year vision set out when the Roadmap was launched, and it is time to assess to what degree policies have changed since then, and identify those areas that merit further efforts by stakeholders to achieve a better environment for better medicines. Two relevant developments have been: 1) the overhaul of the European legislation that governs the conduct of clinical trials in Europe; and 2) our strong involvement in the activities of the Alliance for Biomedical Research in Europe, which recently advocated for radical change in the way the health research priorities are set in the framework of Horizon 2020, the 7-year European Union
Incidence and Prognostic Impact of FoxP3+ Regulatory T Cells in Human Gliomas
Authors: Amy B. Heimberger, Mohamed Abou-Ghazal, Chantal Reina-Ortiz, David S. Yang, Wei Sun, Wei Qiao, Nobuyoshi Hiraoka, Gregory N. Fuller
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The incidence of regulatory T cells (Treg) in intrinsic central nervous system malignancies is unknown. Immunotherapeutic approaches that inhibit the Treg population may be limited to a subset of patients with gliomas. Our hypothesis is that only the most malignant gliomas have a prominent glioma-infiltrating Treg population that contributes to the immunosuppressive biology and that the presence of Tregs is a negative prognostic variable. Experimental Design: We measured the incidence of Tregs in 135 glial tumors (including all pathologic types) in a glioma microarray using immunohistochemical analysis. Results were categorized according to the total number of Tregs within the tumors. Correlation of the presence of Tregs with prognosis was evaluated using univariate and multivariate analyses. Results: Tregs were not present in normal brain tissue and were very rarely found in low-grade gliomas and oligodendrogliomas. We observed significant differences in the prevalence of Tregs between astrocytic and oligodendroglial tumors, between tumors of different grades, and between different pathologic types of tumors. We identified Tregs most frequently in glioblastoma multiforme (GBM) but very rarely in low-grade astrocytomas. The presence of Tregs within GBMs did not alter the median survival in patients from whom the tumors were obtained. Conclusions: Treg infiltration differed significantly in the tumors according to lineage, pathology, and grade. Tregs seemed to have the highest predilection for tumors of the astrocytic lineage and specifically in the high-grade gliomas, such as GBM. In both univariate and multivariate analysis, the presence of Tregs in GBMs seemed to be prognostically neutral.
Tuberculosis screening of migrants to low-burden nations: insights from evaluation of UK practice
Authors: M. Pareek, I. Abubakar, P. J. White, G. P. Garnett, A. Lalvani
Journal: European Respiratory Journal (2010)

Tuberculosis (TB) primarily occurs in the foreign-born in European countries, such as the UK, where increasing notifications and the high proportion of foreign-born cases has refocused attention on immigrant (new entrant) screening. We investigated how UK primary care organisations (PCOs) screen new entrants and whether this differs according to TB burden in the PCOs (incidence &lt;20 or ≥20 cases per 100,000 <i>per annum</i>). An anonymous, 20-point questionnaire was sent to all 192 UK PCOs asking which new entrants are screened, who is screened for active TB/latent TB infection (LTBI) and the methods used. Descriptive analyses were undertaken. Categorical responses were compared using the Chi-squared test. 177 (92.2%) out of 192 PCOs responded; all undertook screening action in response to abnormal chest radiographs, but only 107 (60.4%) screened new entrants for LTBI. Few new entrants had active TB diagnosed (median 0.0%, interquartile range (IQR) 0.0–0.5%) but more were identified with LTBI (median 7.85%, IQR 4.30–13.50%). High-burden PCOs were significantly less likely to screen new entrants for LTBI (OR 0.26, 95% CI 0.12–0.54; p&lt;0.0001). Among PCOs screening for LTBI, there was substantial deviation from national guidance in selection of new entrant subgroups and screening method. Considerable heterogeneity and deviation from national guidance exist throughout the UK new entrant screening process, with high-burden regions undertaking the least screening. Forming an accurate picture of current front-line practice will help to inform future development of European new entrant screening policy.
Adaptive Signature Design: An Adaptive Clinical Trial Design for Generating and Prospectively Testing A Gene Expression Signature for Sensitive Patients
Authors: Boris Freidlin, Richard Simon
Journal: Clinical Cancer Research (2005)

A new generation of molecularly targeted agents is entering the definitive stage of clinical evaluation. Many of these drugs benefit only a subset of treated patients and may be overlooked by the traditional, broad-eligibility approach to randomized clinical trials. Thus, there is a need for development of novel statistical methodology for rapid evaluation of these agents.We propose a new adaptive design for randomized clinical trials of targeted agents in settings where an assay or signature that identifies sensitive patients is not available at the outset of the study. The design combines prospective development of a gene expression-based classifier to select sensitive patients with a properly powered test for overall effect.Performance of the adaptive design, relative to the more traditional design, is evaluated in a simulation study. It is shown that when the proportion of patients sensitive to the new drug is low, the adaptive design substantially reduces the chance of false rejection of effective new treatments. When the new treatment is broadly effective, the adaptive design has power to detect the overall effect similar to the traditional design. Formulas are provided to determine the situations in which the new design is advantageous.Development of a gene expression-based classifier to identify the subset of sensitive patients can be prospectively incorporated into a randomized phase III design without compromising the ability to detect an overall effect.
Infiltration of COX-2–expressing macrophages is a prerequisite for IL-1β–induced neovascularization and tumor growth
Authors: Shintaro Nakao, Takashi Kuwano, Chikako Tsutsumi-Miyahara, Shu-ichi Ueda, Yusuke N. Kimura, Shinjiro Hamano, Koh-hei Sonoda, Yasuo Saijo, Toshihiro Nukiwa, Robert M. Strieter, Tatsuro Ishibashi, Michihiko Kuwano, Mayumi Ono
Journal: Journal of Clinical Investigation (2005)

Inflammatory angiogenesis is a critical process in tumor progression and other diseases. The inflammatory cytokine IL-1beta promotes angiogenesis, tumor growth, and metastasis, but its mechanisms remain unclear. We examined the association between IL-1beta-induced angiogenesis and cell inflammation. IL-1beta induced neovascularization in the mouse cornea at rates comparable to those of VEGF. Neutrophil infiltration occurred on day 2. Macrophage infiltration occurred on days 4 and 6. The anti-Gr-1 Ab-induced depletion of infiltrating neutrophils did not affect IL-1beta- or VEGF-induced angiogenesis. The former was reduced in monocyte chemoattractant protein-1-deficient (MCP-1(-/-)) mice compared with wild-type mice. After day 4, clodronate liposomes, which kill macrophages, reduced IL-1beta-induced angiogenesis and partially inhibited VEGF-induced angiogenesis. Infiltrating macrophages near the IL-1beta-induced neovasculature were COX-2 positive. Lewis lung carcinoma cells expressing IL-1beta (LLC/IL-1beta) developed neovasculature with macrophage infiltration and enhanced tumor growth in wild-type but not MCP-1(-/-) mice. A COX-2 inhibitor reduced tumor growth, angiogenesis, and macrophage infiltration in LLC/IL-1beta. Thus, macrophage involvement might be a prerequisite for IL-1beta-induced neovascularization and tumor progression.
In Vivo Echocardiographic Detection of Enhanced Left Ventricular Function in Gene-Targeted Mice With Phospholamban Deficiency
Authors: Brian D. Hoit, Saeb F. Khoury, Evangelia G. Kranias, Nancy Ball, Richard A. Walsh
Journal: Circulation Research (1995)

Abstract We evaluated the ability of M-mode and Doppler echocardiography to assess left ventricular (LV) function reliably and repeatedly in mice and tested whether these techniques could detect physiological alterations in phospholamban (PLB)–deficient mice. Anesthetized wild-type mice (n=7) and mice deficient in PLB (n=8) were studied with two-dimensional guided M-mode and Doppler echocardiography using a 9-MHz imaging and 5- to 7.5-MHz Doppler transducer. Data were acquired in the baseline state and after intraperitoneal isoproterenol administration (2.0 μg/g IP). Interobserver and intraobserver variability and reproducibility were excellent. PLB-deficient mice were associated with significant ( P &lt;.05) increases in several physiological parameters (mean±SD) compared with wild-type control mice: normalized mean velocity of circumferential shortening (7.7±2.1 versus 5.5±1.0 circ/sec), peak aortic velocity (105±13 versus 75±9.2 cm/s), mean aortic acceleration (57±16 versus 31±4 m/s 2 ), and peak early-diastolic transmitral velocity (80.0±7.2 versus 66.9±7.7 cm/s). LV dimensions, shortening fractions, heart rates, late diastolic transmitral (A) velocities, and early to late (E/A) diastolic velocity ratios were similar in both groups. Isoproterenol administration resulted in significant increases in Doppler indices of ventricular function in control but not PLB-deficient mice. These findings indicate that assessment of LV function can be performed noninvasively in mice under varying physiological conditions and that PLB regulates basal LV function in vivo.
Myopericarditis Following Smallpox Vaccination Among Vaccinia-Naive US Military Personnel
Authors: Jeffrey S. Halsell
Journal: JAMA (2003)

ContextIn the United States, the annual incidence of myocarditis is estimated at 1 to 10 per 100 000 population. As many as 1% to 5% of patients with acute viral infections involve the myocardium. Although many viruses have been reported to cause myopericarditis, it has been a rare or unrecognized event after vaccination with the currently used strain of vaccinia virus (New York City Board of Health).ObjectiveTo describe a series of probable cases of myopericarditis following smallpox vaccination among US military service members reported since the reintroduction of vaccinia vaccine.Design, Setting, ParticipantsSurveillance case definitions are presented. The cases were identified either through sentinel reporting to US military headquarters surveillance using the Defense Medical Surveillance System or reports to the Vaccine Adverse Event Reporting System using International Classification of Diseases, Ninth Revision. The cases occurred among individuals vaccinated from mid-December 2002 to March 14, 2003.Main Outcome MeasureElevated serum levels of creatine kinase (MB isoenzyme), troponin I, and troponin T, usually in the presence of ST-segment elevation on electrocardiogram and wall motion abnormalities on echocardiogram.ResultsAmong 230 734 primary vaccinees, 18 cases of probable myopericarditis after smallpox vaccination were reported (an incidence of 7.8 per 100 000 over 30 days). No cases of myopericarditis following smallpox vaccination were reported among 95 622 vaccinees who were previously vaccinated. All cases were white men aged 21 years to 33 years (mean age, 26.5 years), who presented with acute myopericarditis 7 to 19 days following vaccination. A causal relationship is supported by the close temporal clustering (7-19 days; mean, 10.5 days following vaccination), wide geographic and temporal distribution, occurrence in only primary vaccinees, and lack of evidence for alternative etiologies or other diseases associated with myopericarditis. Additional supporting evidence is the observation that the observed rate of myopericarditis among primary vaccinees is 3.6-fold (95% confidence interval, 3.33-4.11) higher than the expected rate among personnel who were not vaccinated. The background incidence of myopericarditis did not show statistical significance when stratified by age (20-34 years: 2.18 expected cases per 100 000; 95% confidence interval [CI], 1.90-2.34), race (whites: 1.82 per 100 000; 95% CI, 1.50-2.01), and sex (males: 2.28 per 100 000; 95% CI, 2.04-2.54).ConclusionAmong US military personnel vaccinated against smallpox, myopericarditis occurred at a rate of 1 per 12 819 primary vaccinees. Myopericarditis should be considered an expected adverse event associated with smallpox vaccination. Clinicians should consider myopericarditis in the differential diagnosis of patients presenting with chest pain 4 to 30 days following smallpox vaccination and be aware of the implications as well as the need to report this potential adverse advent.
Targeted delivery of Neurogenin-2 protein in the treatment for cerebral ischemia-reperfusion injury
Authors: Bin Deng, Xingchun Gou, Hai Chen, Liya Li, Haixing Zhong, Hao Xu, Fengliang Jiang, Zhijing Zhao, Qiang Wang, Lixian Xu
Journal: Biomaterials (2013)
Mutations in BRAF and KRAS Characterize the Development of Low-Grade Ovarian Serous Carcinoma
Authors: G. Singer, R. Oldt, Y. Cohen, B. G. Wang, D. Sidransky, R. J. Kurman, I.-M. Shih
Journal: JNCI Journal of the National Cancer Institute (2003)

Activating mutations in KRAS and in one of its downstream mediators, BRAF, have been identified in a variety of human cancers. To determine the role of mutations in BRAF and KRAS in ovarian carcinoma, we analyzed both genes for three common mutations (at codon 599 of BRAF and codons 12 and 13 of KRAS). Mutations in either codon 599 of BRAF or codons 12 and 13 of KRAS occurred in 15 of 22 (68%) invasive micropapillary serous carcinomas (MPSCs; low-grade tumors) and in 31 of 51 (61%) serous borderline tumors (precursor lesions to invasive MPSCs). None of the tumors contained a mutation in both BRAF and KRAS. In contrast, none of the 72 conventional aggressive high-grade serous carcinomas analyzed contained the BRAF codon 599 mutation or either of the two KRAS mutations. The apparent restriction of these BRAF and KRAS mutations to low-grade serous ovarian carcinoma and its precursors suggests that low-grade and high-grade ovarian serous carcinomas develop through independent pathways.
Persistent, Biologically Meaningful Prostate Cancer After 1 Year of Androgen Ablation and Docetaxel Treatment
Authors: Vassiliki Tzelepi, Eleni Efstathiou, Sijin Wen, Patricia Troncoso, Maria Karlou, Curtis A. Pettaway, Louis L. Pisters, Anh Hoang, Christopher J. Logothetis, Lance C. Pagliaro
Journal: Journal of Clinical Oncology (2011)

Clinicians are increasingly willing to treat prostate cancer within the primary site in the presence of regional lymph node or even limited distant metastases. However, no formal study on the merits of this approach has been reported. We used a preoperative clinical discovery platform to prioritize pathways for assessment as therapeutic targets and to test the hypothesis that the primary site harbors potentially lethal tumors after aggressive treatment.Patients with locally advanced or lymph node-metastatic prostate cancer underwent 1 year of androgen ablation and three cycles of docetaxel therapy, followed by prostatectomy. All specimens were characterized for stage by accepted criteria. Expression of select molecular markers implicated in disease progression and therapy resistance was determined immunohistochemically and compared with that in 30 archived specimens from untreated patients with high-grade prostate cancer. Marker expression was divided into three groups: intracellular signaling pathways, stromal-epithelial interaction pathways, and angiogenesis.Forty patients were enrolled, 30 (75%) of whom underwent prostatectomy and two (5%) who underwent cystoprostatectomy. Twenty-nine specimens contained sufficient residual tumor for inclusion in a tissue microarray. Immunohistochemical analysis showed increased epithelial and stromal expression of CYP17, SRD5A1, and Hedgehog pathway components, and modulations of the insulin-like growth factor I pathway.A network of molecular pathways reportedly linked to prostate cancer progression is activated after 1 year of therapy; biomarker expression suggests that potentially lethal cancers persist in the primary tumor and may contribute to progression.
Severity and outcome of cystic lung disease in women with tuberous sclerosis complex
Authors: Angelo M. Taveira-DaSilva, Amanda M. Jones, Patricia Julien-Williams, Jianhua Yao, Mario Stylianou, Joel Moss
Journal: European Respiratory Journal (2014)

What are the clinical features, severity, and rate of progression of lung disease in women with tuberous sclerosis and lymphangioleiomyomatosis (LAM) and how do they differ from patients with sporadic LAM? Data from 94 tuberous sclerosis/LAM and 460 sporadic LAM women were compared. 40 tuberous sclerosis/LAM and 40 sporadic LAM patients were age- and lung function-matched, and changes in volume occupied by cysts (cyst score) and pulmonary function occurring over 6.5 years were evaluated. Tuberous sclerosis/LAM patients had better lung function than sporadic LAM patients, but no difference was observed from sporadic LAM patients in yearly rates of change in forced expiratory volume in 1 s (−1.9±2.7 versus −1.9±1.9% predicted; p=0.302), diffusing capacity of the lung for CO (−2.1±2.8 versus −1.9±2.7% predicted; p=0.282) or cyst scores (+1.0±1.3 versus +1.4±1.7%, p=0.213). However, the proportion of patients with abnormal lung function and higher rates of FEV 1 decline was greater in sporadic LAM. Some young tuberous sclerosis/LAM patients (mean age 25.7±3 years) progressed rapidly from minimal to severe lung disease. Tuberous sclerosis/LAM patients may experience abrupt declines in lung function. Consequently, women with tuberous sclerosis found to have lung cysts should undergo periodic functional and radiological testing to follow disease progression and determine need for therapy.
Chronic Electrical Neuronal Stimulation Increases Cardiac Parasympathetic Tone by Eliciting Neurotrophic Effects
Authors: Obaida R. Rana, Erol Saygili, Christopher Gemein, Matthias D.H. Zink, Alexandra Buhr, Esra Saygili, Karl Mischke, Kay W. Nolte, Joachim Weis, Christian Weber, Nikolaus Marx, Patrick Schauerte
Journal: Circulation Research (2011)

Rationale: Recently, we provided a technique of chronic high-frequency electric stimulation (HFES) of the right inferior ganglionated plexus for ventricular rate control during atrial fibrillation in dogs and humans. In these experiments, we observed a decrease of the intrinsic ventricular rate during the first 4 to 5 months when HFES was intermittently shut off. Objective: We thus hypothesized that HFES might elicit trophic effects on cardiac neurons, which in turn increase baseline parasympathetic tone of the atrioventricular node. Methods and Results: In mongrel dogs atrial fibrillation was induced by rapid atrial pacing. Endocardial HFES of the right inferior ganglionated plexus, which contains abundant fibers to the atrioventricular node, was performed for 2 years. Sham-operated nonstimulated dogs served as control. In chronic neurostimulated dogs, we found an increased neuronal cell size accompanied by an increase of choline acetyltransferase and unchanged tyrosine hydroxylase protein expression as compared with unstimulated dogs. Moreover, β-nerve growth factor (NGF) and neurotrophin (NT)-3 were upregulated in chronically neurostimulated dogs. In vitro, HFES of cultured neurons of interatrial ganglionated plexus from adult rats increased neuronal growth accompanied by upregulation of NGF, NT-3, glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) expression. NGF was identified as the main growth-inducing factor, whereas NT-3 did not affect HFES-induced growth. However, NT-3 could be identified as an important acetylcholine-upregulating factor. Conclusions: HFES of cardiac neurons in vivo and in vitro causes neuronal cellular hypertrophy, which is mediated by NGF and boosters cellular function by NT-3–mediated acetylcholine upregulation. This knowledge may contribute to develop HFES techniques to augment cardiac parasympathetic tone.
<i>Pten</i> Inactivation and the Emergence of Androgen-Independent Prostate Cancer
Authors: Michael M. Shen, Cory Abate-Shen
Journal: Cancer Research (2007)

Abstract Hormone refractory disease represents a late-stage and generally lethal event in prostate tumorigenesis. Analyses of mouse models have recently shown that the onset of hormone independence can be uncoupled from disease progression and is associated with activation of the phosphoinositide-3 kinase/Akt as well as Erk mitogen-activated protein kinase signaling pathways in the prostate epithelium, which act in part to counterbalance the inhibitory effects of androgen receptor signaling in the prostate stroma. These observations have potential implications for the treatment of patients with hormone refractory cancer and highlight the role of epithelial-stromal interactions for androgen independence. [Cancer Res 2007;67(14):6535–8]