tbuckley/cabot-search huggingface dataset:
Sorafenib enriches epithelial cell adhesion molecule–positive tumor initiating cells and exacerbates a subtype of hepatocellular carcinoma through TSC2‐AKT cascade
Authors: Dong‐Xian Guan, Jie Shi, Yang Zhang, Jiang‐Sha Zhao, Ling‐Yun Long, Tian‐Wei Chen, Er‐Bin Zhang, Yuan‐Yuan Feng, Wen‐Dai Bao, Yue‐Zhen Deng, Lin Qiu, Xue‐Li Zhang, H. Phillip Koeffler, Shu‐qun Cheng, Jing‐Jing Li, Dong Xie
Journal: Hepatology (2015)

Sorafenib is a specific adenosine triphosphate–competitive RAF inhibitor used as a first‐line treatment of advanced hepatocellular carcinoma (HCC). However, the responses are variable, reflecting heterogeneity of the disease, while the resistance mechanism remains poorly understood. Here, we report that sorafenib treatment can exacerbate disease progression in both patient‐derived xenografts and cell line–derived xenografts and that the therapeutic effect of the drug inversely covaries to the ratio of epithelial cell adhesion molecule–positive cells, which may be tumor initiating cells in HCC. The TSC2‐AKT cascade mediates this sorafenib resistance. In response to sorafenib treatment, formation of the TSC1/2 complex is enhanced, causing increased phosphorylation of AKT, which contributes to up‐regulation of “stemness”‐related genes in epithelial cell adhesion molecule–positive cells and enhancement of tumorigenicity. The expression of TSC2 negatively correlated with prognosis in clinical sorafenib therapy. Furthermore, all‐ trans retinoic acid decreased AKT activity, reduced the epithelial cell adhesion molecule–positive cell population enriched by sorafenib, and potentiated the therapeutic effect of sorafenib in the patient‐derived xenograft model. Conclusion : Our findings suggest that a subtype of HCC is not suitable for sorafenib therapy; this resistance to sorafenib can be predicted by the status of TSC2, and agents inducing differentiation of tumor initiating cells (e.g., all‐ trans retinoic acid) should improve the prognosis of this subtype of HCC.(H epatology 2015;62:1791–1803)
Monounsaturated Fat–Rich Diet Prevents Central Body Fat Distribution and Decreases Postprandial Adiponectin Expression Induced by a Carbohydrate-Rich Diet in Insulin-Resistant Subjects
Authors: J.A. Paniagua, A. Gallego de la Sacristana, I. Romero, A. Vidal-Puig, J.M. Latre, E. Sanchez, P. Perez-Martinez, J. Lopez-Miranda, F. Perez-Jimenez
Journal: Diabetes Care (2007)

Central obesity is associated with insulin resistance through factors that are not fully understood. We studied the effects of three different isocaloric diets on body fat distribution, insulin sensitivity, and peripheral adiponectin gene expression.Eleven volunteers, offspring of obese type 2 diabetic patients with abdominal fat deposition, were studied. These subjects were considered insulin resistant as indicated by Matsuda index values <4 after an oral glucose tolerance test, and they maintained A1C <6.5% without therapeutic intervention. All subjects underwent three dietary periods of 28 days each in a crossover design: 1) diet enriched in saturated fat (SAT), 2) diet rich in monounsaturated fat (MUFA) (Mediterranean diet), and 3) diet rich in carbohydrates (CHOs).Weight, body composition, and resting energy expenditure remained unchanged during the three sequential dietary periods. Using dual-energy X-ray absorptiometry we observed that when patients were fed a CHO-enriched diet, their fat mass was redistributed toward the abdominal depot, whereas periphery fat accumulation decreased compared with isocaloric MUFA-rich and high-SAT diets (ANOVA P < 0.05). Changes in fat deposition were associated with decreased postprandial mRNA adiponectin levels in peripheral adipose tissue and lower insulin sensitivity index values from a frequently sampled insulin-assisted intravenous glucose tolerance test in patients fed a CHO-rich diet compared with a MUFA-rich diet (ANOVA P < 0.05).An isocaloric MUFA-rich diet prevents central fat redistribution and the postprandial decrease in peripheral adiponectin gene expression and insulin resistance induced by a CHO-rich diet in insulin-resistant subjects.
Humeral Stress Periostitis The Arm Equivalent of ???Shin Splints
Authors: N D GREYSON
Journal: Clinical Nuclear Medicine (1995)

Subacute stress or repetitive over-exertion produces osteoblastic reaction at the bony insertions of the affected muscles. Stress periostitis is a mild phase in the continuum of traumatic injuries which could progress to true fractures. Most commonly seen in the tibiae of runners or aerobic dancers, this report illustrates a tennis player and a baseball pitcher with stress periosteal reactions in their humeri, suggesting that mechanisms analogous to "shin splints" may be operative in the arm.
Recent Therapeutic Advances in the Treatment of Colorectal Cancer
Authors: Kristen K. Ciombor, Christina Wu, Richard M. Goldberg
Journal: Annual Review of Medicine (2014)

Metastatic colorectal cancer is a prevalent disease for which novel targeted therapies and biologically based combinations are under development. Cytotoxic chemotherapy doublets (FOLFOX, FOLFIRI) and triplets (FOLFOXIRI) in combination with biologics are standard regimens, and efforts are ongoing to delineate the optimal sequence for each patient based on unique underlying tumor biology. Molecular profiling of metastatic colorectal cancer (including mutational analysis for KRAS, NRAS, BRAF, PIK3CA, and others) has become increasingly important for identification of prognostic and predictive biomarkers, as well as for insights into the biology that drives the tumor. Large comprehensive analyses such as that of The Cancer Genome Atlas have provided important clues into carcinogenesis and discerned potentially druggable targets for metastatic colorectal cancer. Novel therapeutic agents currently under investigation for subtypes of this disease include immunotherapies such as anti-programmed cell death receptor antibody, cancer stem cell inhibitors, targeted combinations such as BRAF and PI3K inhibitors, and the anti-RAS reovirus Reolysin®.
Psychotropic drugs inhibit swarming in Proteus spp. and related genera
Authors: S. Muñoz-Criado, J.L. Muñoz-Bellido, M.A. Alonso-Manzanares, M.N. Gutiérrez-Zufiaurre, J.A. García-Rodríguez
Journal: Clinical Microbiology and Infection (1998)
Asymmetric breast uptake of radioiodine in a patient with thyroid malignancy: metastases or not?
Authors: A Sinha, K M Bradley, J Steatham, A Weaver
Journal: Journal of the Royal Society of Medicine (2008)

Various physiological processes can cause potentially misleading appearances in radioiodine whole body scans; proper understanding of the causes of these can therefore obviate diagnostic errors. Whole-body radioiodine scintigraphy with I131 or I123 is an accurate form of imaging used for management of differentiated thyroid carcinoma. Following thyroidectomy, any residual thyroid tissue or metastatic disease is ablated with high dose I131 and diagnostic images are acquired, demonstrating residual thyroid tissue and metastatic disease. However, atypical physiological uptake of I131 can simulate metastases.
Clinical and radiological characteristics of lung disease in inflammatory bowel disease
Authors: R Mahadeva, G Walsh, CD Flower, JM Shneerson
Journal: European Respiratory Journal (2000)

The pulmonary associations of inflammatory bowel disease (IBD) are poorly characterized. The clinical, physiological and high-resolution computed tomographic thorax characteristics of the lung disease in patients with IBD presenting with respiratory symptoms are described. Detailed clinical information was obtained and standard pulmonary physiological tests and thorax high-resolution computed tomography performed on 14 patients with ulcerative colitis (UC) and three with Crohn's disease (CD), 10 male, aged 38-83 yrs. Respiratory symptoms had been present for 2-50 yrs and extraintestinal manifestations were present in three (17.6%). Normal pulmonary physiology (six patients) was associated with the high resolution computed tomographic changes of bronchiectasis, mosaic perfusion and air trapping suggestive of obliterative bronchiolitis and a pattern of centrilobular nodules and branching linear opacities ("tree in bud" appearance) suggestive of either cellular bronchiolitis or bronchiolectasis with mucoid secretions. Bronchiectasis was found in 13 patients (11 UC, 2 CD), 11 had air trapping and five had a "tree in bud" appearance on computed tomography. One patient had a predominantly peripheral reticular pattern at the lung bases similar to that found in cryptogenic fibrosing alveolitis and one patient had a mixed reticular and ground-glass pattern in the midzones with a patchy distribution in the central and peripheral portions of the lungs with air trapping. Eleven patients (three with alveolitis) exhibited a clinical and/or physiological response to steroids. Pulmonary abnormalities in ulcerative colitis and Crohn's disease can present years after the onset of the bowel disease and can affect any part of the lungs. Early recognition is important as they can be strikingly steroid-responsive.
Inhibition of allograft inflammatory factor-1 expression reduces development of neointimal hyperplasia and p38 kinase activity
Authors: Laura J. Sommerville, Chen Xing, Sheri E. Kelemen, Satoru Eguchi, Michael V. Autieri
Journal: Cardiovascular Research (2008)

AimsAllograft inflammatory factor-1 (AIF-1) is a calcium-binding, scaffold-signalling protein expressed in vascular smooth muscle cells (VSMCs) in response to injury. The effects of AIF-1 attenuation on development of intimal hyperplasia are unknown, and the molecular mechanisms of these effects remain uncharacterized. The goals of the present study were to determine whether AIF-1 knockdown reduced VSMC proliferation, migration, and intimal hyperplasia, and determine AIF-1 effects on signal transduction in VSMCs.
The amazing universe of hepatic microstructure†
Authors: Valeer J. Desmet
Journal: Hepatology (2009)

An informal review is presented by the author of his 50 years of involvement in practice and research in hepatopathology. Some background for the author's attitude and meandering pathway into his professional career serves as introduction to a short discussion of the main topics of his interest and expertise. Histogenesis of liver cancer was the theme of early work for a Ph.D. thesis, the results of which were lost into oblivion due to local rules and circumstances, but were rescued three decades later. His conclusions about the cells of origin of liver cancer remain concordant with the newer concepts in the field after nearly half a century. Studies in the field of chronic hepatitis became a long saga, involving the first classification of this syndrome by "the Gnomes" in 1968, histochemical investigations of viral antigens, lymphocyte subsets and adhesion molecules, and a quarter century later, the creation of a new classification presently in use. Cholestasis was a broadening field in diagnostic entities and involved the study of liver lesions, comprising pathways of bile regurgitation (including reversed secretory polarity of hepatocytes) and so-called ductular reaction. The latter topic has a high importance for the various roles it plays in modulating liver tissue of chronic cholestasis into biliary cirrhosis, and as the territory of hepatic progenitor cells, crucial for liver regeneration in adverse conditions and in development of liver cancer. Study of the embryology of intrahepatic bile ducts helped to clarify the strange appearance of the ducts in "ductal plate configuration" in several conditions, including some forms of biliary atresia with poor prognosis and all varieties of fibrocystic bile duct diseases with "ductal plate malformation" as the basic morphologic lesion.
A Growth Hormone Receptor Mutation Impairs Growth Hormone Autofeedback Signaling in Pituitary Tumors
Authors: Sylvia L. Asa, Rebecca DiGiovanni, Jing Jiang, Megan L. Ward, Kimberly Loesch, Shozo Yamada, Toshiaki Sano, Katsuhiko Yoshimoto, Stuart J. Frank, Shereen Ezzat
Journal: Cancer Research (2007)

Abstract Pituitary tumors are a diverse group of neoplasms that are classified based on clinical manifestations, hormone excess, and histomorphologic features. Those that cause growth hormone (GH) excess and acromegaly are subdivided into morphologic variants that have not yet been shown to have pathogenetic significance or predictive value for therapy and outcome. Here, we identify a selective somatic histidine-to-leucine substitution in codon 49 of the extracellular domain of the GH receptor (GHR) in a morphologic subtype of human GH-producing pituitary tumors that is characterized by the presence of cytoskeletal aggresomes. This GHR mutation significantly impairs glycosylation-mediated receptor processing, maturation, ligand binding, and signaling. Pharmacologic GH antagonism recapitulates the morphologic phenotype of pituitary tumors from which this mutation was identified, inducing the formation of cytoskeletal keratin aggresomes. This novel GHR mutation provides evidence for impaired hormone autofeedback in the pathogenesis of these pituitary tumors. It explains the lack of responsiveness to somatostatin analogue therapy of this tumor type, in contrast to the exquisite sensitivity of tumors that lack aggresomes, and has therapeutic implications for the safety of GH antagonism as a therapeutic modality in acromegaly. [Cancer Res 2007;67(15):7505–11]
Reply to C. Zhuang et al
Authors: Robin H. Kennedy, E. Anne Francis, Rose Wharton, Philip Quirke, Nicholas P. West, Jane M. Blazeby, Susan J. Dutton
Journal: Journal of Clinical Oncology (2014)

We thank Zhuang et al 1 for their interest in the EnROL (Enhanced Recovery Open Versus Laparoscopic) trial 2 and appreciate the opportunity to clarify the points that they raised.Zhuang et al were concerned that compliance with early oral feeding, early mobilization, and optimized analgesia was low in the enhanced recovery program (ERP) in the trial.They suggested that low compliance with specific aspects of an ERP means that the trial is underpowered and that more work is still needed.Although it is important to consider which aspects of an ERP are most critical to patient recovery, the concerns of Zhuang et al are not well founded because EnROL aimed to compare laparoscopy with open surgery, and the application of and compliance within the ERP was similar in both groups of the trial; therefore, the treatment effect that was reported is likely to be robust.To date, there have been limited data reported on compliance with enhanced recovery interventions within randomized controlled trials (RCTs).The results of the EnROL trial are similar to those reported for the LAFA (Laparoscopy and/or Fast Track) trial, 3,4 which is the only other similar, multicenter RCT.Maximum differences would be postulated to be seen within a single-center study, but the advantage of multicenter research is that it reflects clinical effectiveness and thus is more representative of practice generally.More than 30 items were included in the EnROL trial, 5 although compliance measurement was limited to the 20 items that were recommended by the international expert collaborative advisory group on enhanced recovery care (Enhanced Recovery After Surgery Society [ERAS]) to make data collection manageable.This is, to our knowledge, more than has ever previously been reported.Although the administration of antiemetics was not measured, their use has been standard practice within the United Kingdom for many years.EnROL was a pragmatic trial and allowed a certain amount of variability between centers, as one would expect in real-world practice.As a result, the trial aimed to maximize the generalizability and translation of results while maintaining scientific rigor and integrity.Some researchers might concur with Zhuang et al 1 that more well-designed and conducted RCTs are important to validate these findings and increase evidence-based practice in surgery worldwide.Others might take the view that recruitment for a similar trial is becoming increasingly difficult as patients become better informed, and surgeons would be better occupied in gaining competence in laparoscopic colorectal surgery so that their patients might benefit from its advantages.
EULAR recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis
Authors: Alexandra N Colebatch, Christopher John Edwards, Mikkel Østergaard, Désirée van der Heijde, Peter V Balint, Maria-Antonietta D'Agostino, Kristina Forslind, Walter Grassi, Espen A Haavardsholm, Glenn Haugeberg, Anne-Grethe Jurik, Robert BM Landewé, Esperanza Naredo, Philip J O'Connor, Ben Ostendorf, Kristina Potočki, Wolfgang A Schmidt, Josef S Smolen, Sekib Sokolovic, Iain Watt, Philip G Conaghan
Journal: Annals of the Rheumatic Diseases (2013)

Objective To develop evidence-based recommendations on the use of imaging of the joints in the clinical management of rheumatoid arthritis (RA). Methods The task force comprised an expert group of rheumatologists, radiologists, methodologists and experienced rheumatology practitioners from 13 countries. Thirteen key questions on the role of imaging in RA were generated using a process of discussion and consensus. Imaging modalities included were conventional radiography, ultrasound, MRI, CT, dual-emission x-ray absorptiometry, digital x-ray radiogrammetry, scintigraphy and positron emission tomography. Research evidence was searched systematically for each question using MEDLINE, EMBASE and Cochrane CENTRAL. The experts used the evidence obtained from the relevant studies to develop a set of 10 recommendations. The strength of recommendation was assessed using a visual analogue scale. Results A total of 6888 references was identified from the search process, from which 199 studies were included in the systematic review. Ten recommendations were produced encompassing the role of imaging in making a diagnosis of RA, detecting inflammation and damage, predicting outcome and response to treatment, monitoring disease activity, progression and remission. The strength of recommendation for each proposition varied according to both the research evidence and expert opinion. Conclusions Ten key recommendations for the role of imaging in the management of RA were developed using research-based evidence and expert opinion.
Biphasic Restitution of Action Potential Duration and Complex Dynamics in Ventricular Myocardium
Authors: Mari Watanabe, Niels F. Otani, Robert F. Gilmour
Journal: Circulation Research (1995)

Abstract The purpose of this study was to determine whether biphasic restitution of action potential duration (APD) in ventricular muscle permits the development of complex dynamic behavior. Such behavior is expected because of the steep ascending slope of restitution and the presence of a maximum. Action potentials recorded from strips of epicardial muscle in which biphasic APD restitution occurred demonstrated a characteristic pattern of phase locking during progressive shortening of the pacing cycle length. 1:1 locking was replaced by irregular dynamics, which in turn was replaced by higher order periodic behavior (eg, 8:8 locking), then by 2:2 locking, and finally by 2:1 locking. Similar patterns of dynamic behavior were produced in a computer model by using a piecewise linear approximation of biphasic APD restitution. Features of APD restitution that were critical determinants of irregular dynamics included the slopes of the ascending and the nonmonotonic regions. These results suggest that rate-related alterations of APD and refractoriness may be affected significantly by small nonmonotonicities in APD restitution.
Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.
Authors: B Fisher, J Bryant, N Wolmark, E Mamounas, A Brown, E R Fisher, D L Wickerham, M Begovic, A DeCillis, A Robidoux, R G Margolese, A B Cruz, J L Hoehn, A W Lees, N V Dimitrov, H D Bear
Journal: Journal of Clinical Oncology (1998)

PURPOSE To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P &lt; .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.
Non–IgE-mediated chronic allergic skin inflammation revealed with rBet v 1 fragments
Authors: Raffaela Campana, Nadine Mothes, Ingrid Rauter, Susanne Vrtala, Renate Reininger, Margarete Focke-Tejkl, Christian Lupinek, Nadja Balic, Susanne Spitzauer, Rudolf Valenta
Journal: Journal of Allergy and Clinical Immunology (2008)