tbuckley/cabot-search huggingface dataset:
Heterogeneous Blood–Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer
Authors: Paul R. Lockman, Rajendar K. Mittapalli, Kunal S. Taskar, Vinay Rudraraju, Brunilde Gril, Kaci A. Bohn, Chris E. Adkins, Amanda Roberts, Helen R. Thorsheim, Julie A. Gaasch, Suyun Huang, Diane Palmieri, Patricia S. Steeg, Quentin R. Smith
Journal: Clinical Cancer Research (2010)

Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood-tumor barrier (BTB) is compromised in many brain metastases; however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain.Experimental brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune-compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy.Analysis of over 2,000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) showed partial BTB permeability compromise in greater than 89% of lesions, varying in magnitude within and between metastases. Brain metastasis uptake of ¹⁴C-paclitaxel and ¹⁴C-doxorubicin was generally greater than normal brain but less than 15% of that of other tissues or peripheral metastases, and only reached cytotoxic concentrations in a small subset (∼10%) of the most permeable metastases. Neither drug significantly decreased the experimental brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was associated with vascular remodeling and correlated with overexpression of the pericyte protein desmin.This work shows that the BTB remains a significant impediment to standard chemotherapeutic delivery and efficacy in experimental brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations.
Transgenic Rabbit Model for Human Troponin I–Based Hypertrophic Cardiomyopathy
Authors: Atsushi Sanbe, Jeanne James, Volkan Tuzcu, Selman Nas, Lisa Martin, James Gulick, Hanna Osinska, Sadayappan Sakthivel, Raisa Klevitsky, Kenneth S. Ginsburg, Donald M. Bers, Bruce Zinman, Edward G. Lakatta, Jeffrey Robbins
Journal: Circulation (2005)

Transgenic and gene-targeted models have focused on the mouse. Fundamental differences between the mouse and human exist in Ca2+ handling during contraction/relaxation and in alterations in Ca2+ flux during heart failure, with the rabbit more accurately reflecting the human system.Cardiac troponin I (cTnI) mutations can cause familial hypertrophic cardiomyopathy. An inhibitory domain mutation, arginine146-->glycine (cTnI(146Gly)), was modeled with the use of transgenic expression in the rabbit ventricle. cTnI(146Gly) levels >40% of total cTnI were perinatally lethal, whereas replacement levels of 15% to 25% were well tolerated. cTnI(146Gly) expression led to a leftward shift in the force-pCa2+ curves with cardiomyocyte disarray, fibrosis, and altered connexin43 organization. In isolated cTnI(146Gly) myocytes, twitch relaxation amplitudes were smaller than in normal cells, but [Ca]i transients and sarcoplasmic reticulum Ca2+ load were not different. Detrended fluctuation analysis of the QT(max) intervals was used to evaluate the cardiac repolarization phase and showed a significantly higher scaling exponent in the transgenic animals.Expression of modest amounts of cTnI(146Gly) led to subtle defects without severely affecting cardiac function. Aberrant connexin organization, subtle morphological deficits, and an altered fractal pattern of the repolarization phase of transgenic rabbits, in the absence of entropy or other ECG abnormalities, may indicate an early developing pathology before the onset of more obvious repolarization abnormalities or major alterations in cardiac mechanics.
Phenotypic correction of von Willebrand disease type 3 blood-derived endothelial cells with lentiviral vectors expressing von Willebrand factor
Authors: Simon F. De Meyer, Karen Vanhoorelbeke, Marinee K. Chuah, Inge Pareyn, Veerle Gillijns, Robert P. Hebbel, Désiré Collen, Hans Deckmyn, Thierry VandenDriessche
Journal: Blood (2006)
Impact of Glycemic Control Strategies on the Progression of Diabetic Peripheral Neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort
Authors: Rodica Pop-Busui, Jiang Lu, Maria Mori Brooks, Stewart Albert, Andrew D. Althouse, Jorge Escobedo, Jenifer Green, Pasquale Palumbo, Bruce A. Perkins, Fred Whitehouse, Teresa L.Z. Jones
Journal: Diabetes Care (2013)

OBJECTIVE The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS DPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score &amp;gt;2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates. RESULTS Results are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62 ± 9 years, mean HbA1c 7.7 ± 1.6%, diabetes duration 10 ± 9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P = 0.02), which remained significant after adjusting for the in-trial HbA1c (P = 0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58–0.99], P &amp;lt; 0.01). CONCLUSIONS Among patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.
Sleep disordered breathing in an adult with cherubism
Authors: S Ladhani
Journal: Thorax (2003)

Sleep disordered breathing in an adult with cherubismCherubism is a rare disorder with bilateral enlargement of the mandible that regresses with time.Bone degrading osteoclasts and bone building osteoblasts function abnormally causing the changes.It is an autosomal dominant condition which manifests in early childhood by the age of 2-5 years, but later regresses with time.Airway obstruction occurs due to backward displacement of the tongue affecting respiration.An 18 year old male was referred to us for snoring.On inquiry the mother reported swelling of the lower face since childhood, which had progressed to its present size.The patient had difficulty in speech, mastication, and swallowing with mental retardation.There was a history of excessive daytime somnolence, nocturia, and increased irritability during the previous few years.On examination he had characteristic features of cherubism.The lower eyelids were retracted and his oral examination revealed gingival hypertrophy with most of the upper and lower teeth embedded in the gums.The tongue was enlarged and the posterior pharyngeal wall could not be visualised.Fine needle aspiration biopsy of the mandible revealed the presence of giant cells with fibrous tissue.A diagnostic record of night time recording of respiratory variables was performed which showed the presence of snoring and an apnoea/ hypopnoea index (AHI) of 12/hour associated with oxygen desaturation.A second study was performed with nasal continuous positive airway pressure (CPAP) of 7 cm H 2 O, following which AHI reduced to 3/hour with no oxygen desaturation or snoring.Obstructive sleep apnoea has been reported only once earlier in a 5 year old boy who was treated with tracheostomy. 1 This is the second report associating cherubism with obstructive sleep apnoea and mental retardation, and the first report of an adult who responded to CPAP therapy.
Safety and Efficacy of Conbercept in Neovascular Age-Related Macular Degeneration
Authors: Xiaoxin Li, Gezhi Xu, Yusheng Wang, Xun Xu, Xiaoling Liu, Shibo Tang, Feng Zhang, Junjun Zhang, Luosheng Tang, Quan Wu, Delun Luo, Xiao Ke
Journal: Ophthalmology (2014)

To assess the safety and efficacy of multiple injections of 0.5 and 2.0 mg conbercept using variable dosing regimens in patients with neovascular age-related macular degeneration (AMD).Randomized, double-masked, multicenter, controlled-dose, and interval-ranging phase 2 clinical trial divided into a 3-month loading phase followed by a maintenance phase.Patients with choroidal neovascularization secondary to AMD with lesion sizes of 12 disc areas or less and a best-corrected visual acuity (BCVA) letter score of between 73 and 24 were enrolled.Patients were randomized 1:1 to receive either 0.5 or 2.0 mg intravitreal conbercept for 3 consecutive monthly does. After the third dose, each group was reassigned randomly again to monthly (Q1M group) or as-needed (pro re nata [PRN] group) treatment without changing the drug assignment.The primary end point was the mean change in BCVA from baseline to month 3, with secondary end points being the mean change in BCVA, mean change in central retinal thickness (CRT), and safety at month 12.We enrolled 122 patients. At the primary end point at month 3, mean improvements in BCVA from baseline in the 0.5- and 2.0-mg groups were 8.97 and 10.43 letters, respectively. At month 12, mean improvements in BCVA from baseline were 14.31, 9.31, 12.42, and 15.43 letters for the 0.5-mg PRN, 0.5-mg Q1M, 2.0-mg PRN, and 2.0-mg Q1M regimens, respectively. At month 12, mean reductions in CRT in the 4 regimens were 119.8, 129.7, 152.1, and 170.8 μm, respectively. There were no significant differences for the pairwise comparisons between all study groups. The difference in the number of injections between the 2 PRN groups was not statistically significant. Treatment with conbercept generally was safe and well tolerated.The significant gains in BCVA at 3 months were the same or better at 12 months in all conbercept dosing groups of neovascular AMD patients. During the 12 months, repeated intravitreal injections of conbercept were well tolerated in these patients. Future clinical trials are required to confirm its long-term efficacy and safety.
Development and Characterization of HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma Tumorgrafts
Authors: Randall J. Kimple, Paul M. Harari, Alexandra D. Torres, Robert Z. Yang, Benjamin J. Soriano, Menggang Yu, Eric A. Armstrong, Grace C. Blitzer, Molly A. Smith, Laurel D. Lorenz, Denis Lee, David T. Yang, Timothy M. McCulloch, Gregory K. Hartig, Paul F. Lambert
Journal: Clinical Cancer Research (2012)

To develop a clinically relevant model system to study head and neck squamous cell carcinoma (HNSCC), we have established and characterized a direct-from-patient tumorgraft model of human papillomavirus (HPV)-positive and HPV-negative cancers.Patients with newly diagnosed or recurrent HNSCC were consented for donation of tumor specimens. Surgically obtained tissue was implanted subcutaneously into immunodeficient mice. During subsequent passages, both formalin-fixed/paraffin-embedded as well as flash-frozen tissues were harvested. Tumors were analyzed for a variety of relevant tumor markers. Tumor growth rates and response to radiation, cisplatin, or cetuximab were assessed and early passage cell strains were developed for rapid testing of drug sensitivity.Tumorgrafts have been established in 22 of 26 patients to date. Significant diversity in tumorgraft tumor differentiation was observed with good agreement in degree of differentiation between patient tumor and tumorgraft (Kappa 0.72). Six tumorgrafts were HPV-positive on the basis of p16 staining. A strong inverse correlation between tumorgraft p16 and p53 or Rb was identified (Spearman correlations P = 0.085 and P = 0.002, respectively). Significant growth inhibition of representative tumorgrafts was shown with cisplatin, cetuximab, or radiation treatment delivered over a two-week period. Early passage cell strains showed high consistency in response to cancer therapy between tumorgraft and cell strain.We have established a robust human tumorgraft model system for investigating HPV-positive and HPV-negative HNSCC. These tumorgrafts show strong correlation with the original tumor specimens and provide a powerful resource for investigating mechanisms of therapeutic response as well as preclinical testing.
Inhibition of lung epithelial cell proliferation by hyperoxia. Posttranscriptional regulation of proliferation-related genes.
Authors: A Clement, M Edeas, K Chadelat, J S Brody
Journal: Journal of Clinical Investigation (1992)

The alveolar surface of the lung is a major target for oxidant injury. After injury, repair of the alveolar epithelium is dependent on the ability of epithelial type 2 (T2) cells to proliferate. The regulation of T2 cell proliferation and the effect of reactive oxygen (O2) species on this lung cell proliferation have not been well defined. To investigate this process we focused on the regulation of two late cell cycle genes, histone and thymidine kinase, in T2 cells and fibroblasts exposed in vitro to varying periods of hyperoxia (95% O2). Hyperoxia for 24 to 48 h arrested cell proliferation in a SV40T-immortalized T2 cell line we have developed and in primary and SV40T-immortalized lung fibroblasts. Despite the cessation of proliferation, histone and TK mRNA continued to be expressed at high levels; mRNA half-lives were markedly prolonged but neither protein was translated. Thus proliferation arrest induced by hyperoxia was associated with posttranscriptional control of at least two late cell cycle-related genes. This form of proliferation arrest is also seen when primary and SV40T-T2 cells but not fibroblasts are serum deprived, suggesting that T2 cells in vitro may be uniquely sensitive to alterations in their redox state and that these alterations in turn affect translational control of a subset of proliferation-related genes.
Inhaling habits among smokers of different types of cigarette.
Authors: N J Wald, M Idle, J Boreham, A Bailey
Journal: Thorax (1980)

Inhaling habits were studied in 1316 men who freely smoked their usual brands of cigarette. An index of inhaling was calculated for each person by dividing the estimated increase in carboxyhaemoglobin level from a standard number of cigarettes by the carbon monoxide yield of the cigarette smoked. Smokers of ventilated filter cigarettes inhaled 82% more than smokers of plain cigarettes (p less than 0.001) and those who smoked unventilated filter cigarettes inhaled 36% more (p less than 0.001). Cigarette consumption was similar among smokers of each type of cigarette. Assuming that the intake of tar and nicotine is proportional to the inhaling index, the intake in either group of filter cigarette smokers would have been less than that in plain cigarette smokers. Among smokers of unventilated cigarettes, however, the intake would not have been much less.
A role for human skin–resident T cells in wound healing
Authors: Antoine Toulon, Lionel Breton, Kristen R. Taylor, Mayer Tenenhaus, Dhaval Bhavsar, Caroline Lanigan, Ross Rudolph, Julie Jameson, Wendy L. Havran
Journal: The Journal of Experimental Medicine (2009)

Epidermal T cells have been shown to play unique roles in tissue homeostasis and repair in mice through local secretion of distinct growth factors in the skin. Human epidermis contains both alphabeta(+) and gammadelta(+) T cells whose functional capabilities are not understood. We demonstrate that human epidermal T cells are able to produce insulin-like growth factor 1 (IGF-1) upon activation and promote wound healing in a skin organ culture model. Moreover, an analysis of the functional capabilities of T cells isolated from acute versus chronic wounds revealed a striking difference. Both alphabeta(+) and Vdelta1(+) T cells isolated from acute wounds actively produced IGF-1, demonstrating that they are activated during tissue damage to participate in wound repair. In contrast, IGF-1 production could not be detected in T cells isolated from chronic wounds. In fact, skin T cells isolated from chronic wounds were refractory to further stimulation, suggesting an unresponsive state. Collectively, these results define a novel role for human epidermis-resident T cells in wound healing and provide new insight into our understanding of chronic wound persistence.
Variability and Accuracy in Mammographic Interpretation Using the American College of Radiology Breast Imaging Reporting and Data System
Authors: K. Kerlikowske, D. Grady, J. Barclay, V. Ernster, S. D. Frankel, S. H. Ominsky, E. A. Sickles
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Several studies, which were limited by their small sample size and selection of difficult cases for review, have reported substantial variability among radiologists in interpretation of mammographic examinations. We have determined, in the largest study to date, intraobserver and interobserver agreement in interpreting screening mammography and accuracy of mammography by use of the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS). Methods: The mammographic examinations were randomly selected on the basis of original mammographic interpretation and cancer outcome from 71 713 screening examinations performed by the Mobile Mammography Screening Program of the University of California, San Francisco, during the period from April 1985 through February 1995. The final sample included 786 abnormal examinations with no cancer detected, 267 abnormal examinations with cancer detected, and 1563 normal examinations. Films were read separately by two radiologists according to BI-RADS. Cancer status was determined by contacting women's physicians and by linkage to the regional Surveillance, Epidemiology, and End Results Program. Results: There was moderate agreement between radiologists in reporting the presence of a finding when cancer was present (k = 0.54) and substantial agreement when cancer was not present (k = 0.62). Agreement was moderate in assigning one of the five assessment categories but was statistically significantly lower when cancer was present relative to when cancer was not present (k = 0.46 versus 0.56; two-sided P = .02). Agreement for reporting the presence of a finding and mammographic assessment was twofold more likely for examinations with less dense breasts. Agreement was higher on repeat readings by the same radiologists than between radiologists. The sensitivity of mammography was lower with BI-RADS than with the original system for mammographic interpretation, but the positive predictive value of mammography was higher. Conclusion: Considerable variability in interpretation of mammographic examinations exists; this variability and the accuracy of mammography are neither improved nor diminished with use of BI-RADS.
Prevention of Sudden Cardiac Death With Implantable Cardioverter-Defibrillators in Children and Adolescents With Hypertrophic Cardiomyopathy
Authors: Barry J. Maron, Paolo Spirito, Michael J. Ackerman, Susan A. Casey, Christopher Semsarian, N.A. Mark Estes, Kevin M. Shannon, Euan A. Ashley, Sharlene M. Day, Giuseppe Pacileo, Francesco Formisano, Emmanuela Devoto, Aristidis Anastasakis, J. Martijn Bos, Anna Woo, Camillo Autore, Robert H. Pass, Giuseppe Boriani, Ross F. Garberich, Adrian K. Almquist, Mark W. Russell, Luca Boni, Stuart Berger, Martin S. Maron, Mark S. Link
Journal: Journal of the American College of Cardiology (2013)
Smoking rates in the Middle-East and North Africa: Interim results of the BREATHE study
Authors: Mehmet Polatli, Mohamed Awad Tageldin, Arshad Javed, Ashraf Alzaabi, Naeem Shahrour, Samya Taright, Majed Beji, Nathir M. Obeidat, Esra Uzaslan, Abdelkader El-Hasnaoui
Journal: European Respiratory Journal (2011)

Background: Smoking is the main risk factor for the development of COPD.

Objectives: This epidemiological study aimed to assess the prevalence and burden of COPD, chronic bronchitis and smoking in 11 countries in the Middle East and North Africa (Algeria, Morocco, Tunisia, Egypt, Jordan, Lebanon, Saudi Arabia, Syria, UAE, Pakistan and Turkey).

Methods: A general population sample of 10 000 subjects ≥ 40yrs in each country was generated from random phone numbers. A structured interview was proposed to all subjects by telephone. Screening questions was used to identify potential subjects with COPD. Individuals who have a life time of smoking ≥ 10 pack-yrs and who either had a diagnosis of COPD or symptoms of chronic bronchitis were considered to have possible COPD. This interim analysis assesses smoking habits of the study population.

Results: 44892 subjects were interviewed and 14034 subjects were smokers. This reflects a prevalence of smoking of 31.4% [95%CI: 31.0-31.8%], ranging from 14.9% [95%CI: 13.5-16.5%] in Pakistan to 48.8% [95%CI: 47.1-50.4%] in Lebanon. The rate of smoking ≥10 pack-yrs was 22.8% [95%CI: 22.4-23.2%]. Smoking was more frequent in men (50.9%; 95%CI: 50.2-51.6%) than in women (15.6%;95%CI: 15.1-16.0%). No relevant differences in smoking rates were found between age groups: 31.6% in subjects aged 40-49yrs, 32.2% in those aged 50-59yrs and 29.4% in those aged ≥60yrs. The use of water-pipes alone was reported by 605 smokers (4.3%), and 442 (3.1%) used both water-pipes and cigarettes.

Conclusion: Smoking is more frequent in men than in women, but rates vary considerably between different countries in the Middle East and North Africa. This may have an impact on health status.