tbuckley/cabot-search huggingface dataset:
Having Pancreatic Cancer with Tumoral Loss of ATM and Normal TP53 Protein Expression Is Associated with a Poorer Prognosis
Authors: Haeryoung Kim, Burcu Saka, Spencer Knight, Michael Borges, Erica Childs, Alison Klein, Christopher Wolfgang, Joseph Herman, Volkan N. Adsay, Ralph H. Hruban, Michael Goggins
Journal: Clinical Cancer Research (2014)

To determine how often loss of ataxia-telangiectasia-mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance.The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival.Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27-5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response.Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection.
Does generalised ligamentous laxity increase seasonal incidence of injuries in male first division club rugby players?
Authors: D R Stewart, S B Burden
Journal: British Journal of Sports Medicine (2004)

Objectives: To investigate if ligamentous laxity increases seasonal incidence of injury in male first division club rugby players, and to determine if strength protects against injury in hypermobile and tight players. Methods: Fifty one male first division club rugby players were examined for ligamentous laxity using the Beighton-Horan assessment and graded with an overall laxity score ranging from 0 (tight) to 9 (hyperlax). Each participant was classified into a group determined by their laxity score: tight (0–3), hypermobile (4–6), or excessively hypermobile (7–9). The incidence of joint injuries was recorded prospectively throughout the rugby season and correlated with laxity score. Differences between the groups were analysed. Results: The overall prevalence of generalised joint hypermobility was 24% (12/51). The incidence of injuries was significantly higher in hypermobile (116.7 per 1000 hours) than tight (43.6 per 1000 hours) players (p = 0.034). There were no significant differences in peak strength between the hypermobile and tight groups. Conclusions: The laxity of the players may explain the differences in injury rates between these groups. Peak strength does not protect the hypermobile joint against injury. It appears that hypermobility may cause an increase in the injury rate of male first division club rugby players.
Treatment of rheumatoid arthritis: strategies for achieving optimal outcomes
Authors: Allan Gibofsky, Yusuf Yazici
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Background:</h3> Mitral regurgitation (MR) is the second leading cause of valvular heart disease in the United States behind aortic stenosis. The percutaneous repair of the mitral valve (MitraClip, Abbott, Inc.) has been approved in the United States since 2013 as an alternative to traditional mitral valve surgery. However, many questions are left unanswered about when to perform this procedure and whom to perform it on. <h3>Methods:</h3> We reviewed major published literature on the MitraClip from 2003-2016 to help guide clinical decision-making. A PubMed search was conducted using the phrase “mitraclip” or “percutaneous mitral valve repair” to identify relevant articles pertaining to the clip as well as surgical valve repair. <h3>Results:</h3> The clinical trials EVEREST I and EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) demonstrated the safety and efficacy of the MitraClip but did not prove its superiority to surgical repair in the population studied. Numerous subsequent registries have suggested that the success of the MitraClip varies with the patient population studied. The currently enrolling Cardiovascular Outcomes for Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional MR (COAPT) trial hopes to answer some of these questions. <h3>Conclusion:</h3> The MitraClip is a new and exciting technology for percutaneously treating disease processes traditionally managed with surgery. The future of the clip and its patient population is dependent on further studies.
Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice
Authors: Kengo Tomita, Yuichi Oike, Toshiaki Teratani, Takashi Taguchi, Masaaki Noguchi, Takahiro Suzuki, Akiko Mizutani, Hirokazu Yokoyama, Rie Irie, Hidetoshi Sumimoto, Atsushi Takayanagi, Kiichi Miyashita, Masaki Akao, Mitsuhisa Tabata, Gen Tamiya, Tamiko Ohkura, Toshifumi Hibi
Journal: Hepatology (2008)

It is unclear how hepatic adiponectin resistance and sensitivity mediated by the adiponectin receptor, AdipoR2, contributes to the progression of nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the roles of hepatic AdipoR2 in NASH, using an animal model. We fed C57BL/6 mice a methionine-deficient and choline-deficient (MCD) diet for up to 8 weeks and analyzed changes in liver pathology caused by either an AdipoR2 short hairpin RNA-expressing adenovirus or an AdipoR2-overexpressing adenovirus. Inhibition of hepatic AdipoR2 expression aggravated the pathological state of NASH at all stages: fatty changes, inflammation, and fibrosis. In contrast, enhancement of AdipoR2 expression in the liver improved NASH at every stage, from the early stage to the progression of fibrosis. Inhibition of AdipoR2 signaling in the liver diminished hepatic peroxisome proliferator activated receptor (PPAR)-alpha signaling, with decreased expression of acyl-CoA oxidase (ACO) and catalase, leading to an increase in lipid peroxidation. Hepatic AdipoR2 overexpression had the opposite effect. Reactive oxygen species (ROS) accumulation in liver increases hepatic production of transforming growth factor (TGF)-beta1 at all stages of NASH; adiponectin/AdipoR2 signaling ameliorated TGF-beta-induced ROS accumulation in primary cultured hepatocytes, by enhancing PPAR-alpha activity and catalase expression.The adiponectin resistance and sensitivity mediated by AdipoR2 in hepatocytes regulated steatohepatitis progression by changing PPAR-alpha activity and ROS accumulation, a process in which TGF-beta signaling is implicated. Thus, the liver AdipoR2 signaling pathway could be a promising target in treating NASH.
Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients
Authors: Emmanuel Xystrakis, Siddharth Kusumakar, Sandra Boswell, Emma Peek, Zoë Urry, David F. Richards, Tonye Adikibi, Carol Pridgeon, Margaret Dallman, Tuck-Kay Loke, Douglas S. Robinson, Franck J. Barrat, Anne O’Garra, Paul Lavender, Tak H. Lee, Christopher Corrigan, Catherine M. Hawrylowicz
Journal: Journal of Clinical Investigation (2005)

We previously reported that human CD4+ Tregs secrete high levels of IL-10 when stimulated in the presence of dexamethasone and calcitriol (vitamin D3). We now show that following stimulation by allergen, IL-10-secreting Tregs inhibit cytokine secretion by allergen-specific Th2 cells in an IL-10-dependent manner. A proportion of patients with severe asthma fail to demonstrate clinical improvement upon glucocorticoid therapy, and their asthma is characterized as glucocorticoid resistant (SR, abbreviation derived from "steroid resistant"). Dexamethasone does not enhance secretion of IL-10 by their CD4+ T cells. Addition of vitamin D3 with dexamethasone to cultures of SR CD4+ T cells enhanced IL-10 synthesis to levels observed in cells from glucocorticoid-sensitive patients cultured with dexamethasone alone. Furthermore, pretreatment with IL-10 fully restored IL-10 synthesis in these cells in response to dexamethasone. Vitamin D3 significantly overcame the inhibition of glucocorticoid-receptor expression by dexamethasone while IL-10 upregulated glucocorticoid-receptor expression by CD4+ T cells, suggesting potential mechanisms whereby these treatments may overcome poor glucocorticoid responsiveness. We show here that administration of vitamin D3 to healthy individuals and SR asthmatic patients enhanced subsequent responsiveness to dexamethasone for induction of IL-10. This strongly suggests that vitamin D3 could potentially increase the therapeutic response to glucocorticoids in SR patients.
Is it a stroke?
Authors: G. J. Hankey, D. J. Blacker
Journal: BMJ (2015)

Stroke is increasingly common and often fatal or disabling. 1 The absence of a definitive diagnostic test for stroke and the potential for emergency interventions to restore brain perfusion, 2 improve survival free of handicap, and minimise early recurrent stroke 3 mean that doctors need to be able to diagnose acute stroke rapidly and accurately.
Oncogenic G Protein GNAQ Induces Uveal Melanoma and Intravasation in Mice
Authors: Jenny Li-Ying Huang, Oscar Urtatiz, Catherine D. Van Raamsdonk
Journal: Cancer Research (2015)

GNAQ and GNA11 are heterotrimeric G protein alpha subunits, which are mutated in a mutually exclusive pattern in most cases of uveal melanoma, one of the most aggressive cancers. Here we introduce the first transgenic mouse model of uveal melanoma, which develops cancers induced by expression of oncogenic GNAQ(Q209L) under control of the Rosa26 promoter. Disease penetrance is 100% by 3 months of age, with 94% of mice also developing lung tumors. In this model, the Yap protein of the Hippo pathway is activated in the eyes, and blood vessels near the lesions in the head and lungs exhibit melanocytic invasion. While full transcription levels are not necessary for GNAQ(Q209L) to transform mouse melanocytes, we obtained suggestive evidence of a selective advantage for increased GNAQ(Q209L) expression in human tumors. Intriguingly, enforced expression of GNAQ(Q209L) progressively eliminated melanocytes from the interfollicular epidermis in adults, possibly explaining the near absence of GNAQ(Q209) mutations in human epithelial melanomas. The mouse model also exhibited dermal nevi and melanocytic neoplasms of the central nervous system, accompanied by impaired hearing and balance, identifying a novel role for GNAQ in melanocyte-like cells of the inner ear. Overall, this model offers a new tool to dissect signaling by oncogenic GNAQ and to test potential therapeutics in an in vivo setting where GNAQ(Q209L) mutations contribute to both the initiation and metastatic progression of uveal melanoma.
Nanostructured Architectures by Assembling Polysaccharide‐Coated BSA Nanoparticles for Biomedical Application
Authors: Zhenming Wang, Kefeng Wang, Xiong Lu, Chen Li, Lu Han, Chaoming Xie, Yaling Liu, Shuxin Qu, Guanming Zhen
Journal: Advanced Healthcare Materials (2015)

Nanostructured architectures are produced on Ti surfaces by layer‐by layer (LbL) self‐assembling of polysaccharide‐coated BSA nanoparticles (BNPs), which created cellular microenvironments mimicking natural extracellular matrix. The BMP‐2 encapsulated BNPs are prepared by a desolvation method, and are further coated by chitosan (CHI) coatings to obtain positively charged NPs (CBNPs). Vancomycin (Van) encapsulated CBNPs are obtained by the same method and subsequently coated by oxidized alginate (OALG) to obtain negatively charged NPs (OCBNPs). The CBNPs and OCBNPs are assembled on Ti surfaces to construct nanostructured coatings via electrostatic and covalent interactions. The nanostructured architectures realize the sustained release of BMP‐2 and Van for a long term. Bone marrow stromal cells (BMSCs) culture tests confirm that the bare nanostructured architectures intrinsically facilitate attachment, proliferation, and differentiation of cells, which is attributed to the nanoscale porous structures that are similar to the size of cellular filopodia. Incorporating BMP‐2 into the nanostructured architectures significantly enhances osteogenetic differentiation of BMSCs, which reveals the synergistic effects of nanostructures and growth factors on cell activity. The antibacterial tests indicate that controlled release of Van has good antibacterial ability against Staphylococcus epidermidis , while not affecting the normal biological activity of BMSCs.
Induction chemotherapy followed by gefitinib and concurrent thoracic radiotherapy for unresectable locally advanced adenocarcinoma of the lung: a multicenter feasibility study (JCOG 0402)
Authors: S. Niho, Y. Ohe, S. Ishikura, S. Atagi, A. Yokoyama, Y. Ichinose, H. Okamoto, K. Takeda, T. Shibata, T. Tamura, N. Saijo, M. Fukuoka
Journal: Annals of Oncology (2012)
Treatment of recalcitrant pustular psoriasis with infliximab: effective reduction of chemokine expression
Authors: S. Benoit, A. Toksoy, E-B. Brocker, R. Gillitzer, M. Goebeler
Journal: British Journal of Dermatology (2004)

Tumour necrosis factor (TNF)-α is thought to play a major role in the pathophysiology of psoriasis. Good clinical responses of psoriasis to anti-TNF-α-based therapies have recently been demonstrated. We studied the effect of infliximab, a monoclonal antibody against TNF-α, on chemokine expression in pustular psoriasis. A 61-year-old man with a 2-year history of severe pustular psoriasis of von Zumbusch type who did not respond to conventional therapies responded rapidly to treatment with infliximab. The clinical response was reflected by an immediate and effective reduction of the neutrophil-attractant chemokines interleukin (IL)-8 and growth-related oncogene (Gro)-α as well as of monocyte chemoattractant protein (MCP)-1, as determined by mRNA in situ hybridization of lesional skin. No expression before or after treatment was seen for monokine induced by interferon (IFN)-γ (MIG) and IFN-inducible protein (IP)-10. Thus, in pustular psoriasis the chemokine expression pattern is dominated by neutrophil-attractant chemokines and MCP-1 while, in contrast to plaque psoriasis, IFN-γ-inducible lymphocyte-attractant chemokines such as IP-10 and MIG are not abundant. We conclude that anti-TNF-α treatment with infliximab is an effective therapy in severe pustular psoriasis which is reflected by downregulation of disease-promoting chemokines such as IL-8, Gro-α and MCP-1.
Myocardial apoptosis and ischemic preconditioning
Authors: Z Zhao
Journal: Cardiovascular Research (2002)

Necrosis and apoptosis are two forms of cell death in the myocardium that have been associated with ischemia and reperfusion. Although it has been well documented that necrosis, as a major form of myocyte cell death, rapidly leads to a destruction of a large group of cells after myocardial ischemia and reperfusion, the induction of apoptosis in myocardium, primarily triggered during reperfusion, may independently contribute to the extension of cell death (i.e. infarction) in a dynamic manner. Ischemic preconditioning (IP), an endogenous protective mechanism rapidly evoked by a brief period of ischemia, is recognized for its protection in limiting myocardial necrosis, but has also shown a profound inhibition in apoptosis. While much research has been done on the reduction of necrosis by IP, there remains no clear understanding of the time course of inhibition of apoptosis by IP after long-term reperfusion. In this review, we will show the time course of necrosis and apoptosis during reperfusion, focus on the role of apoptosis in the extension of lethal myocyte injury, and summarize the potential mechanisms involved in reducing apoptosis by IP. ‘Classic’ or ‘early’ IP has been shown to reduce apoptosis in part by inhibiting inflammatory cell activation and altering the expression of anti- and pro-apoptotic proteins as well as protein kinase C activity. It remains unknown, however, whether delayed IP participates in the attenuation of apoptosis in addition to necrosis. The demonstration of a ‘window of opportunity’ in inhibiting apoptosis by IP will provide new directions in research investigating mechanisms underlying myocyte cell death during reperfusion, and translate this information into new treatment approaches for reducing the extent of ischemia/reperfusion injury.
Association of insulin and insulin-like growth factors with Barrett's oesophagus
Authors: Katarina B Greer, Cheryl L Thompson, Lacie Brenner, Beth Bednarchik, Dawn Dawson, Joseph Willis, William M Grady, Gary W Falk, Gregory S Cooper, Li Li, Amitabh Chak
Journal: Gut (2011)

<h3>Background</h3> It is postulated that high serum levels of insulin and insulin growth factor 1 (IGF-1) mediate obesity-associated carcinogenesis. The relationship of insulin, IGF-1 and IGF binding proteins (IGFBP) with Barrett9s oesophagus (BO) has not been well examined. <h3>Methods</h3> Serum levels of insulin and IGFBPs in patients with BO were compared with two separate control groups: subjects with gastro-oesophageal reflux disease (GORD) and screening colonoscopy controls. Fasting insulin, IGF-1 and IGFBPs were assayed in the serum of BO cases (n=135), GORD (n=135) and screening colonoscopy (n=932) controls recruited prospectively at two academic hospitals. Logistic regression was used to estimate the risk of BO. <h3>Results</h3> Patients in the highest tertile of serum insulin levels had an increased risk of BO compared with colonoscopy controls (adjusted OR 2.02, 95% CI 1.15 to 3.54) but not compared with GORD controls (adjusted OR 1.55, 95% CI 0.76 to 3.15). Serum IGF-1 levels in the highest tertile were associated with an increased risk of BO (adjusted OR 4.05, 95% CI 2.01 to 8.17) compared with the screening colonoscopy control group but were not significantly different from the GORD control group (adjusted OR 0.57, 95% CI 0.27 to 1.17). IGFBP-1 levels in the highest tertile were inversely associated with a risk of BO in comparison with the screening colonoscopy controls (adjusted OR 0.11, 95% CI 0.05 to 0.24) but were not significantly different from the GORD control group (adjusted OR 1.04, 95% CI 0.49 to 2.16). IGFBP-3 levels in the highest tertile were inversely associated with the risk of BO compared with the GORD controls (OR 0.36, 95% CI 0.16 to 0.81) and also when compared with the colonoscopy controls (OR 0.40, 95% CI 0.20 to 0.79). <h3>Conclusions</h3> These results provide support for the hypothesis that the insulin/IGF signalling pathways have a role in the development of BO.
Cytosolic β-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer's disease
Authors: Lee E Goldstein, Julien A Muffat, Robert A Cherny, Robert D Moir, Maria H Ericsson, Xudong Huang, Christine Mavros, Jennifer A Coccia, Kyle Y Faget, Karlotta A Fitch, Colin L Masters, Rudolph E Tanzi, Leo T Chylack, Ashley I Bush
Journal: The Lancet (2003)
The Hippocampal Formation in Schizophrenia
Authors: Carol A. Tamminga, Ana D. Stan, Anthony D. Wagner
Journal: American Journal of Psychiatry (2010)

The hippocampal formation is one of the most extensively studied regions of the brain, with well-described anatomy and basic physiology; moreover, aspects of human memory mediated by the hippocampus are well characterized. In schizophrenia, alterations in hippocampal anatomy, perfusion, and activation are consistently reported; impairments in declarative memory function, especially in the flexible use of event memories (e.g., in the service of memory-based inference), are common. Postmortem molecular changes suggest a selective reduction in glutamate transmission in the dentate gyrus and in its efferent fibers, the mossy fiber pathway. A reduction in dentate gyrus glutamatergic output and in its information processing functions could generate two co-occurring outcomes in the hippocampus: 1) a change in homeostatic plasticity processes in cornu ammonis 3 (CA3), accompanied by increased activity due to reduced afferent stimulation from the dentate gyrus onto CA3 neurons, a process that could increase the pattern completion functions of CA3, and 2) the loss of mnemonic functions specific to the dentate gyrus, namely pattern separation, a change that could increase the prevalence of illusory pattern completion and reduce discrimination between present and past experiences in memory. The resulting increase in "runaway" CA3-mediated pattern completion could result in cognitive "mistakes," generating psychotic associations and resulting in memories with psychotic content. Tests of this model could result in novel approaches to the treatment of psychosis and declarative memory alterations and in novel animal preparations for basic schizophrenia research.
Prevalence of diverticular disease of the colon in patients with ischaemic heart disease.
Authors: K J Foster, G Holdstock, P J Whorwell, P Guyer, R Wright
Journal: Gut (1978)

In view of the similar patterns of incidence of diverticular disease of the colon (DD) and ischaemic heart disease (IHD) in different communities, the prevalence of diverticular disease was investigated in male patients after recovery from acute myocardial infarction. A significantly higher prevalence of DD was found among infarct patients (57%) than among male control subjects (25%) matched for age and social class.
Who should pay for cancer drugs?
Authors: Ilora Finlay
Journal: Journal of the Royal Society of Medicine (2008)

Co-payments exist in many aspects of health care already. The Department of Health's own website states that 
‘Entitlement to help with health costs (NHS prescription and dental charges, optical and hospital travel costs) is based on the principle that those who can afford to contribute should do so, while those who are likely to have difficulty in paying should be protected.’1
 Prescription charges in England are the clearest example of co-payments, where occasionally the prescription charge is greater than the cost of the drug, although usually the converse is true. Dental charges are in three bands for patients seeing an NHS dentist, but of course it is often difficult to find an NHS dentist and many have left the NHS to practice only privately. But co-payments are also required for eye tests, spectacles and contact lenses, for wigs and fabric supports. Each has a series of potential exemptions but the underlying principle behind the exemptions is ability to pay.