tbuckley/cabot-search huggingface dataset:
Developmental basis for filamin-A-associated myxomatous mitral valve disease
Authors: Kimberly Sauls, Annemarieke de Vlaming, Brett S. Harris, Katherine Williams, Andy Wessels, Robert A. Levine, Susan A. Slaugenhaupt, Richard L. Goodwin, Luigi Michele Pavone, Jean Merot, Jean-Jacques Schott, Thierry Le Tourneau, Thomas Dix, Sean Jesinkey, Yuanyi Feng, Christopher Walsh, Bin Zhou, Scott Baldwin, Roger R. Markwald, Russell A. Norris
Journal: Cardiovascular Research (2012)

We hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development. Filamin-A-deficient mice exhibit abnormally enlarged mitral valves during foetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modelling, 3D morphometry, biochemical studies, and 3D matrix assays, we demonstrate that the inception of the valve disease occurs during foetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during foetal valve gestation is due, in part, to molecular interactions between filamin-A, serotonin, and the cross-linking enzyme, transglutaminase-2 (TG2). Pharmacological and genetic perturbations that inhibit serotonin-TG2-filamin-A interactions lead to impaired ECM remodelling and engender progression to a myxomatous valve phenotype. These findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin-A pathway, regulate matrix organization during foetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease.
Application of sialic acid/polysialic acid in the drug delivery systems
Authors: Ting Zhang, Zhennan She, Zhenjun Huang, Jing Li, Xiang Luo, Yihui Deng
Journal: Asian Journal of Pharmaceutical Sciences (2014)

The properties of modified biomaterial are gaining more and more importance in drug delivery systems. Sialic acid (SA) and polysialic acid (PSA) serve as endogenous substances, which are non-immunogenic and biodegradable. At the same time, SA modification of the drugs/carriers can enhance the uptake of tumor cell and retention in brain; PSA modification can reduce the immunogenicity of the proteins or polypeptides and increase circulation time of the modified drugs/carriers in the blood, thus achieving active targeting effect. These properties offer a variety of opportunities for applications in drug delivery systems. This article summarizes the biological functions of SA and PSA and presents the technologies of SA/PSA modified small molecule drugs, proteins and carriers in drug delivery systems.
Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial
Authors: Casper Steenholdt, Jørn Brynskov, Ole Østergaard Thomsen, Lars Kristian Munck, Jan Fallingborg, Lisbet Ambrosius Christensen, Gitte Pedersen, Jens Kjeldsen, Bent Ascanius Jacobsen, Anne Sophie Oxholm, Jakob Kjellberg, Klaus Bendtzen, Mark Andrew Ainsworth
Journal: Gut (2013)

Although the reasons for secondary loss of response to infliximab (IFX) maintenance therapy in Crohn's disease vary, dose intensification is usually recommended. This study investigated the cost-effectiveness of interventions defined by an algorithm designed to identify specific reasons for therapeutic failure.Randomised, controlled, single-blind, multicentre study. 69 patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) (n=36) or interventions based on serum IFX and IFX antibody levels using the proposed algorithm (n=33). Predefined co-primary end points at week 12 were proportion of patients responding (Crohn's Disease Activity Index (CDAI) decrease ≥ 70, or ≥ 50% reduction in active fistulas) and accumulated costs related to treatment of Crohn's disease, expressed as mean cost per patient, based on the Danish National Patient Registry for all hospitalisation and outpatient costs in the Danish healthcare sector.Costs for intention-to-treat patients were substantially lower (34%) for those treated in accordance with the algorithm than by IFX dose intensification: € 6038 vs € 9178, p<0.001. However, disease control, as judged by response rates, was similar: 58% and 53%, respectively, p=0.81; difference 5% (-19% to 28%). For per-protocol patients, treatment costs were even lower (56%) in the algorithm-treated group (€ 4062 vs € 9178, p<0.001) and with similar response rates (47% vs 53%, p=0.78; difference -5% (-33% to 22%)).Treatment of secondary IFX failure using an algorithm based on combined IFX and IFX antibody measurements significantly reduces average treatment costs per patient compared with routine IFX dose escalation and without any apparent negative effect on clinical efficacy.NCT00851565.
Inhibition of the P2X7 Receptor Reduces Cystogenesis in PKD
Authors: Ming-Yang Chang, Jenn-Kan Lu, Ya-Chung Tian, Yung-Chang Chen, Cheng-Chieh Hung, Yi-Hui Huang, Yau-Hung Chen, Mai-Szu Wu, Chih-Wei Yang, Yi-Chuan Cheng
Journal: Journal of the American Society of Nephrology (2011)

The P2X7 receptor participates in purinergic signaling, which may promote the progression of ADPKD. We examined the effects of a P2X7 receptor antagonist and a P2X7 receptor agonist on cyst development in a zebrafish model of polycystic kidney disease in which we knocked down pkd2 by morpholinos. We used live wt-1b pronephric-specific GFP-expressing zebrafish embryos to directly observe changes in the pronephros. Exposure of pkd2-morphant zebrafish to a P2X7 receptor antagonist (oxidized ATP [OxATP]) significantly reduced the frequency of the cystic phenotype compared with either exposure to a P2X7 receptor agonist (BzATP) or with no treatment (P < 0.01). Histology confirmed improvement of glomerular cysts in OxATP-treated pkd2 morphants. OxATP also reduced p-ERK activity and cell proliferation in pronephric kidneys in pkd2 morphants. Inhibition of P2X7 with an additional specific antagonist (A-438079), and through morpholino-mediated knockdown of p2rx7, confirmed these effects. In conclusion, blockade of the P2X7 receptor reduces cyst formation via ERK-dependent pathways in a zebrafish model of polycystic kidney disease, suggesting that P2X7 antagonists may have therapeutic potential in ADPKD.
Genetic background affects susceptibility in nonfatal pneumococcal bronchopneumonia
Authors: J.A. Preston, K.W. Beagley, P.G. Gibson, P.M. Hansbro
Journal: European Respiratory Journal (2004)

A nonfatal pneumococcal lung infection model was required to investigate immune responses during recovery, and the interaction of other diseases subsequent to infection. A murine model of nonfatal pneumococcal lung infection was developed and the effect of genetic background on susceptibility was determined in BALB/c and C57BL/6 mice. Bacteria colonised the lungs and mice developed mild clinical illness with pathophysiology similar to human bronchopneumonia. Recovery was associated with immune cell influx, which cleared bacteria but induced tissue damage characteristic of pneumococcal bronchopneumonia. After clearance, immune cell populations returned to normal and tissues appeared less inflamed. Although bacterial exposure and clearance were similar, the extent of immune cell influx and tissue damage differed significantly. Larger numbers of neutrophils and lymphocytes entered lung tissue and the affected area was greater in BALB/c compared with C57BL/6 mice. An inflammatory basis for differences was determined with greater levels of phagocytosis and oxidative burst observed in BALB/c mice. C57BL/6 mice cleared the low inoculum with a reduced immune response; however, C57BL/6 mice are more susceptible to larger inocula, which overwhelms the immune system. These different susceptibilities result from a greater inflammatory response in BALB/c compared with C57BL/6 mice.
Decreasing Women's Anxieties After Abnormal Mammograms: A Controlled Trial
Authors: Mary B Barton, Debra S Morley, Sara Moore, Jennifer D Allen, Ken P Kleinman, Karen M Emmons, Suzanne W Fletcher
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Few studies have evaluated interventions to decrease a woman's anxiety after she receives an abnormal mammogram (i.e., one with a recommendation for follow-up). We performed a controlled trial to compare the effects of both an immediate reading of mammograms (i.e., a radiology intervention) and of an educational intervention that taught skills to cope with anxiety on the psychological status of women whose mammograms were normal or abnormal. Methods:Eligible women (n = 8543) aged 39 years or older were recruited from seven mammography sites at the time of their scheduled mammography screening and assigned to receive no intervention, either the radiology or the educational intervention, or both interventions. We used the Impact of Events Scale (IES) and the Hopkins Symptom Checklist subscales for Anxiety (HSC-A) and Depression (HSC-D) in structured telephone interviews of 2844 women to assess the psychological status of all women with abnormal mammograms (excluding women diagnosed with breast cancer) and of a random sample of women with normal mammograms at 3 weeks and 3 months after their mammograms. All statistical tests were two-sided. Results: We obtained usable 3-week interviews for 2390 (84%) women. By the 3-week interview, 1037 (72.1%) of the 1439 interviewed women with abnormal mammograms had completed the recommended work-up and knew that their abnormal mammograms were false positives. Women with abnormal mammograms had higher IES and HSC-A scores (i.e., more anxiety) than women with normal mammograms (mean IES scores: 4.97 [95% confidence interval {CI} = 4.47 to 5.50] and 1.82 [95% CI = 1.51 to 2.14], respectively; P<.001; mean HSC-A scores: 1.14 [95% CI = 1.12 to 1.15] and 1.11 [95% CI = 1.09 to 1.13], respectively, P= .002). Among women with false-positive mammograms, those who had received the radiology intervention reported less anxiety than those who had not (mean IES scores: 4.42 [95% CI = 3.73 to 5.07] and 5.53 [95% CI = 4.82 to 6.28], respectively, P= .026). The educational intervention was not associated with any difference in psychological outcomes. Three months after the mammogram, by which time more than 80% of the women with abnormal results knew their mammograms to be false positives, anxiety levels of women with false-positive mammograms remained higher than those of women with normal mammograms (mean IES scores: 2.34 [95% CI = 1.99 to 2.69] and 1.15 [95% CI = 0.87 to 1.47], respectively, P<.001). Conclusion: Immediate reading of screening mammograms, but not an educational intervention targeting coping skills, was associated with less anxiety among women with false-positive mammograms 3 weeks after mammography.
Corneal Biomechanics and Biomaterials
Authors: Jeffrey W. Ruberti, Abhijit Sinha Roy, Cynthia J. Roberts
Journal: Annual Review of Biomedical Engineering (2011)

The ability to clearly observe one's environment in the visible spectrum provides a tremendous evolutionary advantage in most of the world's habitats. The complex optical processing system that has evolved in higher vertebrate animals gathers, focuses, detects, transduces, and interprets incoming visible light. The cornea resides at the front end of this imaging system, where it provides a clear optical aperture, substantial refractive power, and the structural stability required to protect the fragile intraocular components. Nature has resolved these simultaneous design requirements through an exceedingly clever manipulation of common extracellular-matrix structural materials (e.g., collagen and proteoglycans). In this review, we (a) examine the biophysical and optical roles of the cornea, (b) discuss increasingly popular approaches to altering its natural refractive properties with an emphasis on biomechanics, and (c) investigate the fast-rising science of corneal replacement via synthetic biomaterials. We close by considering relevant open problems that would benefit from the increased attention of bioengineers.
Estrogen Receptor β (ERβ) Level but Not Its ERβcx Variant Helps to Predict Tamoxifen Resistance in Breast Cancer
Authors: Majida Esslimani-Sahla, Joelle Simony-Lafontaine, Andrew Kramar, Roselyne Lavaill, Caroline Mollevi, Margaret Warner, Jan-Åke Gustafsson, Henri Rochefort
Journal: Clinical Cancer Research (2004)

Abstract The antiestrogen tamoxifen, a major endocrine therapy of estrogen receptor (ER)-positive breast cancer, is nevertheless inefficient in 30 to 40% of cases for unknown reasons. We retrospectively studied 50 ER-positive primary breast carcinomas. All of the patients had received tamoxifen as the only adjuvant therapy. They were divided into two groups depending on whether they relapsed within 5 years (16 tamoxifen-resistant cases) or did not relapse within 5 years (34 tamoxifen-sensitive cases). The expression of total ERβ protein, and of ERβcx protein, was estimated anonymously in formalin-fixed, paraffin-embedded tumor sections, by using specific antibodies and quantifiying nuclear immunostaining with a computer image analyzer. All of the tumors were found to be HER-2/neu-negative by immunohistochemistry. Univariate analysis showed that Scarff-Bloom-Richardsson grade modified by Elston (SBR grade; P &amp;lt; 0.001), tumor size (P = 0.042), and MIB-1 proliferation index (P = 0.02) were significantly higher in tamoxifen-resistant tumors. A low level of total ERβ, whether in percentage of positive cells or in quantitative immunocytochemical (QIC) score, was also associated with tamoxifen resistance (P = 0.004). ERβcx expression and lymph node status were similar between the two groups. The expression of ERβ in the total population was positively correlated with ERβcx (r = 0.63, P &amp;lt; 0.001), and was independent of the other parameters. In a multivariate analysis, ERβ expression was the most important variable (P = 0.001), followed by SBR grade (I+II versus III; P = 0.008), and MIB-1 (P = 0.016). To conclude, tamoxifen resistance is associated with classical variables of aggressive tumors (high SBR grade, proliferation index, and tumor size) but not with node invasiveness. Low ERβ level is an additional independent marker, better than ERα level, to predict tamoxifen resistance.
Sustained Drug-Release Patches
Authors: K. Gregory Humma
Journal: JAMA (1982)

To the Editor.—  In the past several months, two drugs (scopolamine and nitroglycerin) have become available in sustained-release patches for application to the skin. This unique new dosage form should enhance compliance, since it increases convenience to the patient; it also provides optimal delivery of drugs that are difficult to administer effectively in ambulatory patients. It should be pointed out, however, that these new products are potentially hazardous in that they may not be recognized as a form of drug therapy when treating the unconscious patient. Both patches are devoid of labeling and resemble in color and size an adhesive bandage and are therefore unobtrusive when worn. Recommended application of the scopolamine patch is to the postauricular area, while the nitroglycerin patch is to be applied to any area devoid of hair, excepting distal portions of the extremities. Both products exert effects for more than 24 hours.  It is important
Non-adherence in difficult asthma: time to take it seriously
Authors: Liam G Heaney, Rob Horne
Journal: Thorax (2011)

Recent studies have demonstrated a high prevalence of non-adherence with anti-inflammatory medication in patients referred for specialist assessment with difficult-to-control asthma. As well as poor asthma outcome and increased healthcare cost, failure to detect non-adherence makes identification of true treatment-resistant/refractory asthma challenging. This is because guideline definitions of refractory asthma are all predicated on failure to respond to high-dose anti-inflammatory therapy but do not state how adherence with this therapy should be assessed. With the advent of novel expensive biological therapies, the systematic identification of non-adherence becomes more essential to avoid targeting therapies at an inappropriate patient group. Novel biomarkers of steroid exposure, in combination with more traditional surrogate measures such as prescription filling assessment, may allow more objective assessments of non-adherence to be developed in the future. When identified, non-adherence can potentially be targeted and improved, but the key challenge is to empower patients to make informed choices about medicines rather than decisions influenced by misplaced beliefs about benefit and harm. There is an urgent need for the systematic development of individualised interventions which allow non-adherence to be effectively managed. Thus, non-adherence must become a priority in the clinical assessment of difficult-to-control asthma because addressing non-adherence is likely to deliver greater benefits in this group than any novel treatment. It is essential that future research examines strategies and interventions to address non-adherence in subjects with difficult-to-control asthma.
Whole genome sequencing of meticillin-resistant Staphylococcus aureus
Authors: Makoto Kuroda, Toshiko Ohta, Ikuo Uchiyama, Tadashi Baba, Harumi Yuzawa, Ichizo Kobayashi, Longzhu Cui, Akio Oguchi, Ken-ichi Aoki, Yoshimi Nagai, JianQi Lian, Teruyo Ito, Mutsumi Kanamori, Hiroyuki Matsumaru, Atsushi Maruyama, Hiroyuki Murakami, Akira Hosoyama, Yoko Mizutani-Ui, Noriko K Takahashi, Toshihiko Sawano, Ryu-ichi Inoue, Chikara Kaito, Kazuhisa Sekimizu, Hideki Hirakawa, Satoru Kuhara, Susumu Goto, Junko Yabuzaki, Minoru Kanehisa, Atsushi Yamashita, Kenshiro Oshima, Keiko Furuya, Chie Yoshino, Tadayoshi Shiba, Masahira Hattori, Naotake Ogasawara, Hideo Hayashi, Keiichi Hiramatsu
Journal: The Lancet (2001)
High liver fibrosis index FIB‐4 is highly predictive of hepatocellular carcinoma in chronic hepatitis B carriers
Authors: Beomseok Suh, Sehhoon Park, Dong Wook Shin, Jae Moon Yun, Hyung‐Kook Yang, Su Jong Yu, Cheong‐Il Shin, Jin‐Soo Kim, Eunmi Ahn, Hyejin Lee, Jin Ho Park, BeLong Cho
Journal: Hepatology (2014)

Screening for hepatocellular carcinoma (HCC) is clinically important given that its early detection has remarkable survival benefits. We investigated the possible role of FIB-4, a recently developed noninvasive marker for liver fibrosis based on routine laboratory tests, as a clinical indicator for predicting future HCC among hepatitis B surface antigen (HBsAg) carriers. Our retrospective cohort study involved 986 Korean HBsAg carriers 40 years of age or older who visited Seoul National University Hospital for a health checkup. National medical service claims data were used to determine HCC incidence. Median follow-up time was 5.4 years (interquartile range: 4.4 years). Adjusted for age, sex, body mass index, smoking, alcohol, and antiviral medication for hepatitis B, compared to subjects with FIB-4 <1.25, subjects with 1.7≤ FIB-4 <2.4 showed an adjusted hazard ratio (aHR) of 4.57 (95% confidence interval [CI]: 1.50-13.92) and subjects with FIB-4 ≥2.4 showed an aHR of 21.34 (95% CI: 7.73-58.92) for HCC incidence. FIB-4 was shown to have incremental predictive value to ultrasonographic liver cirrhosis for HCC incidence (C-index: 0.701 vs. 0.831; P = 0.001). FIB-4 was also better predictive of HCC incidence, compared to that of ultrasonographic liver cirrhosis (C-index: 0.775 vs. 0.701; P = 0.040).High FIB-4 is a highly predictive risk factor for HCC incidence among Korean HBsAg carriers. FIB-4 is a promising, easily applicable, and cost-effective clinical tool in identifying a subpopulation of HBsAg carriers who are at heightened risk. Our study needs to be replicated in larger future studies on various ethnic groups; nonetheless, our study suggests that FIB-4 may play a valuable role in HCC screening among HBsAg carriers.
Raising the Bar for Antineoplastic Agents: How to Choose Threshold Values for Superiority Trials in Advanced Solid Tumors
Authors: Alberto F. Sobrero, Alessandro Pastorino, Daniel J. Sargent, Paolo Bruzzi
Journal: Clinical Cancer Research (2014)

To establish the concept of minimum clinically meaningful outcome (mCMO) of treatment in advanced solid tumors, to establish its threshold and evaluate how many superiority trials of new antineoplastic agents pass this threshold.We chose overall survival as the primary indicator of patient benefit. Four conceptually different types of treatment effect can be identified in OS curves: HR, gains in median OS, proportional, and absolute increases at long-term OS. We postulated threshold levels for these four parameters defining the mCMO and set the bar at three different levels of required benefit: high, medium, and low. The postulated values were then studied by comparing our thresholds with the actual results of the pivotal superiority phase III trials on new drugs reporting on mature OS data.Forty-three trials on 35,419 patients in 12 cancer types on 23 novel agents met these criteria. Only two trials reached the postulated "high" thresholds for HR and median OS. The number of "positive trials" increased to eight and 15 when the bar was lowered to the "medium" and "low" levels, respectively. The same analysis was done for proportional and absolute increases in long-term OS. No trial satisfied the criteria for long-term benefit, whereas only two and nine trials satisfied both parameters for the "medium and low" required benefit levels, respectively.All four OS-related parameters contribute to define the mCMO. If the bar for the mCMO is raised too much, positive trials are exceptional.