tbuckley/cabot-search huggingface dataset:
Long-term Cultures of Bone Marrow–Derived Human Mesenchymal Stem Cells Frequently Undergo Spontaneous Malignant Transformation
Authors: Gro Vatne Røsland, Agnete Svendsen, Anja Torsvik, Ewa Sobala, Emmet McCormack, Heike Immervoll, Josef Mysliwietz, Joerg-Christian Tonn, Roland Goldbrunner, Per Eystein Lønning, Rolf Bjerkvig, Christian Schichor
Journal: Cancer Research (2009)

Abstract Human mesenchymal stem cells (hMSC) aid in tissue maintenance and repair by differentiating into specialized cell types. Due to this ability, hMSC are currently being evaluated for cell-based therapies of tissue injury and degenerative diseases. However, extensive expansion ex vivo is a prerequisite to obtain the cell numbers required for human cell-based therapy protocols. Recent studies indicate that hMSC may contribute to cancer development and progression either by acting as cancer-initiating cells or through interactions with stromal elements. If spontaneous transformation ex vivo occurs, this may jeopardize the use of hMSC as therapeutic tools. Whereas murine MSC readily undergo spontaneous transformation, there are conflicting reports about spontaneous transformation of hMSC. We have addressed this controversy in a two-center study by growing bone marrow–derived hMSC in long-term cultures (5–106 weeks). We report for the first time spontaneous malignant transformation to occur in 45.8% (11 of 24) of these cultures. In comparison with hMSC, the transformed mesenchymal cells (TMC) showed a significantly increased proliferation rate and altered morphology and phenotype. In contrast to hMSC, TMC grew well in soft agar assays and were unable to undergo complete differentiation. Importantly, TMC were highly tumorigenic, causing multiple fast-growing lung deposits when injected into immunodeficient mice. We conclude that spontaneous malignant transformation may represent a biohazard in long-term ex vivo expansion of hMSC. On the other hand, this spontaneous transformation process may represent a unique model for studying molecular pathways initiating malignant transformation of hMSC. [Cancer Res 2009;69(13):5331–9]
Glycoprotein Nonmetastatic Melanoma Protein B, a Potential Molecular Therapeutic Target in Patients with Glioblastoma Multiforme
Authors: Chien-Tsun Kuan, Kenji Wakiya, Jeannette M. Dowell, James E. Herndon, David A. Reardon, Michael W. Graner, Gregory J. Riggins, Carol J. Wikstrand, Darell D. Bigner
Journal: Clinical Cancer Research (2006)

Abstract Purpose: More brain tumor markers are required for prognosis and targeted therapy. We have identified and validated promising molecular therapeutic glioblastoma multiforme (GBM) targets: human transmembrane glycoprotein nonmetastatic melanoma protein B (GPNMBwt) and a splice variant form (GPNMBsv, a 12-amino-acid in-frame insertion in the extracellular domain). Experimental Design: We have done genetic and immunohistochemical evaluation of human GBM to determine incidence, distribution, and pattern of localization of GPNMB antigens in brain tumors as well as survival analyses. Results: Quantitative real-time PCR on 50 newly diagnosed GBM patient tumor samples indicated that 35 of 50 GBMs (70%) were positive for GPNMBwt+sv transcripts and 15 of 50 GBMs (30%) were positive for GPNMBsv transcripts. Normal brain samples expressed little or no GPNMB mRNA. We have isolated and characterized an anti-GPNMB polyclonal rabbit antiserum (2640) and two IgG2b monoclonal antibodies (mAb; G11 and U2). The binding affinity constants of the mAbs ranged from 0.27 × 108 to 9.6 × 108 M−1 measured by surface plasmon resonance with immobilized GPNMB, or 1.7 to 2.1 × 108 M−1 by Scatchard analyses with cell-expressed GPNMB. Immunohistochemical analysis detected GPNMB in a membranous and cytoplasmic pattern in 52 of 79 GBMs (66%), with focal perivascular reactivity in ∼27%. Quantitative flow cytometric analysis revealed GPNMB cell surface molecular density of 1.1 × 104 to 7.8 × 104 molecules per cell, levels sufficient for mAb targeting. Increased GPNMB mRNA levels correlated with elevated GPNMB protein expression in GBM biopsy samples. Univariate and multivariate analyses correlated expression of GPNMB with survival of 39 GBM patients using RNA expression and immunohistochemical data, establishing that patients with relatively high mRNA GPNMB transcript levels (wt+sv and wt), &amp;gt;3-fold over normal brain, as well as positive immunohistochemistry, have a significantly higher risk of death (hazard ratios, 3.0, 2.2, and 2.8, respectively). Conclusions: Increased mRNA and protein levels in GBM patient biopsy samples correlated with higher survival risk; as a detectable surface membrane protein in glioma cells, the data indicate that GPNMB is a potentially useful tumor-associated antigen and prognostic predictor for therapeutic approaches with malignant gliomas or any malignant tumor that expresses GPNMB.
Nupr1-Aurora Kinase A Pathway Provides Protection against Metabolic Stress-Mediated Autophagic-Associated Cell Death
Authors: Tewfik Hamidi, Carla E. Cano, Daniel Grasso, Maria Noé Garcia, Maria José Sandi, Ezequiel L. Calvo, Jean-Charles Dagorn, Gwen Lomberk, Raul Urrutia, Sandro Goruppi, Arkaitz Carracedo, Guillermo Velasco, Juan L. Iovanna
Journal: Clinical Cancer Research (2012)

The limited supply of oxygen and nutrients is thought to result in rigorous selection of cells that will eventually form the tumor.Nupr1 expression pattern was analyzed in human tissue microarray (TMA) and correlated with survival time of the patient. Microarray analysis was conducted on MiaPaCa2 cells subjected to metabolic stress in Nupr1-silenced conditions. DNA repair and cell cycle-associated gene expression was confirmed by real-time quantitative PCR (qRT-PCR). Nupr1 and AURKA protective role were analyzed using RNA interference (RNAi) silencing or overexpression. DNA damage and autophagy were analyzed by Western blot analysis and immunofluorescence.We showed that both Nupr1 and HIF1α are coexpressed in human pancreatic ductal adenocarcinoma (PDAC) samples and negatively correlate with survival time. PDAC-derived cells submitted to hypoxia and/or glucose starvation induce DNA damage-dependent cell death concomitantly to the overexpression of stress protein Nupr1. Affymetrix-based transcriptoma analysis reveals that Nupr1 knockdown enhances DNA damage and alters the expression of several genes involved in DNA repair and cell-cycle progression. Expression of some of these genes is common to hypoxia and glucose starvation, such as Aurka gene, suggesting that Nupr1 overexpression counteracts the transcriptional changes occurring under metabolic stress. The molecular mechanism by which hypoxia and glucose starvation induce cell death involves autophagy-associated, but not caspase-dependent, cell death. Finally, we have found that AURKA expression is partially regulated by Nupr1 and plays a major role in this response.Our data reveal that Nupr1 is involved in a defense mechanism that promotes pancreatic cancer cell survival when exposed to metabolic stress.
Sudden cardiac death by Commotio cordis: role of mechano–electric feedback
Authors: P Kohl
Journal: Cardiovascular Research (2001)

Moderate pre-cordial mechanical impact can cause sudden cardiac death, even in the absence of morphological damage to the heart. This is the most severe expression of a condition termed, in the 19th century, Commotio cordis. Experimental studies performed in the early 1930s showed that sudden cardiac death after chest impact is brought about by an intrinsic cardiac response to the mechanical stimulus. The precise (sub-)cellular mechanisms of this response are still poorly understood. This article summarises experimental findings on the condition and relates them to the more recently established concept of cardiac mechano—electric feedback. As a result, an explanation of the mechanisms that give rise to sudden cardiac death by Commotio cordis and targets for further research are suggested.
Embodied metaphor in perceptual symbols
Authors: Raymond W. Gibbs, Eric A. Berg
Journal: Behavioral and Brain Sciences (1999)

We agree with Barsalou's claim about the importance of perceptual symbols in a theory of abstract concepts. Yet we maintain that the richness of many abstract concepts arises from the metaphorical mapping of recurring patterns of perceptual, embodied experience to provide essential structure to these abstract ideas.
Antifibrotic therapy in pancreatic diseases
Authors: Mert Erkan
Journal: Gut (2012)

In the current study by Ishiwatari et al , a novel antifibrotic therapy has been shown to revert pancreatic fibrosis induced by dibutyltin dichloride and cerulein in rats.1 The authors have previously used this approach to resolve fibrosis in various models of liver cirrhosis in rats.2 The compound used in both studies is an siRNA against collagen-specific chaperone protein gp46 (HSP47 in humans), encapsulated in vitamin A-coupled liposomes (VA-lip-siRNAgp46). This approach exploits the pivotal roles of stellate cells in fibrogenesis as well as in the uptake and storage of vitamin A in the target organs.

Quiescent pancreatic stellate cells (PSC) belong to the stellate cell system consisting of retinoid-storing cells in various organs.3 Upon pancreatic injury or during carcinogenesis, PSC are activated by cytokines, growth factors, reactive oxygen species as well as mechanical factors such as increased intraductal pressure or by a stiff extracellular matrix (ECM). Upon activation, PSC transdifferentiate into a myofibroblast-like phenotype and produce ECM proteins. PSC activation is associated with loss of cytoplasmic vitamin A (retinol) stores.

Activated PSC are responsible for producing the desmoplastic stroma of two major diseases of the pancreas—chronic pancreatitis and pancreatic cancer. Replacement of the normal parenchyma by fibrosis leads to exocrine and endocrine insufficiency in chronic pancreatitis. …
Republished research: Impact of autologous blood injections in treatment of mid-portion Achilles tendinopathy: double blind randomised controlled trial
Authors: Kevin J Bell, Mark L Fulcher, David S Rowlands, Ngaire Kerse
Journal: British Journal of Sports Medicine (2014)

Study question Do peritendinous autologous blood injections improve pain and function in people with mid-portion Achilles tendinopathy? Summary answer The administration of two unguided peritendinous autologous blood injections one month apart, in addition to a standardised eccentric training programme, provides no additional benefit in the treatment of mid-portion Achilles tendinopathy. What is known and what this paper adds Several studies have suggested that injection of autologous blood can help in the treatment of various tendinopathies. There is a lack of high quality evidence showing relevant benefit for autologous blood injections, particularly in the management of mid-portion Achilles tendinopathy. We found no additional reduction in pain or improvement in function when these injections were combined with an eccentric calf training programme.
Natural killer cell phenotype modulation and natural killer/T‐cell interplay in nucleos(t)ide analogue‐treated hepatitis e antigen‐negative patients with chronic hepatitis B
Authors: Carolina Boni, Pietro Lampertico, Lavinia Talamona, Tiziana Giuberti, Federica Invernizzi, Valeria Barili, Paola Fisicaro, Marzia Rossi, Maria Cristina Cavallo, Andrea Vecchi, Giuseppe Pedrazzi, Arianna Alfieri, Massimo Colombo, Gabriele Missale, Carlo Ferrari
Journal: Hepatology (2015)

Natural killer (NK) and hepatitis B virus (HBV)‐specific T cells are functionally impaired in chronic hepatitis B (CHB). Understanding to what extent nucleos(t)ide analogue (NUC) therapy can improve T‐ and NK‐cell responses is important in the perspective of immunomonitoring strategies for a safe and earlier NUC withdrawal and of novel combination therapies based on modulation of antiviral immunity. To gain further insights into T/NK‐cell interplay, we studied NK‐cell phenotype and function in hepatitis B e antigen–negative chronic HBV patients either untreated (25) or NUC treated (36 hepatitis B surface antigen [HBsAg] + and 10 HBsAg – /hepatitis B surface antibody [anti‐HBs] + ). Interferon‐gamma, interleukin‐2, and tumor necrosis factor alpha (TNF‐α) production by HBV‐specific T cells was also analyzed in NUC‐treated patients. NK cells from chronic naïve patients showed an “inflammatory” phenotype defined by increased expression of TNF‐related apoptosis‐inducing ligand (TRAIL), CD38, and Ki67 that significantly declined upon viremia suppression and alanine aminotransferase normalization induced by NUC therapy. Reversion to a quiescent NK‐cell phenotype was associated with restoration of the HBV‐specific T‐cell function. T‐ and NK‐cell responses showed an inverse correlation, with an opposite behavior in individual NUC‐treated patients. NK‐cell depletion as well as TRAIL and NKG2D pathway blockade induced a significant improvement of the HBV‐specific T‐cell function. Conclusions : NK cells can express regulatory activity on T cells in NUC‐treated patients with prevalent inhibition of CD4 T cells, likely needed to limit persistent T‐cell activation. NK‐cell phenotype is modulated by NUC therapy and its reversion to quiescence mirrors efficient HBV‐specific T‐cell responses. Thus, changes of NK‐cell phenotype may predict acquisition of antiviral control before anti‐HBs seroconversion and represent the groundwork for future studies aimed at assessing whether NK phenotyping can be translated into the clinical practice to guide NUC suspension.(H epatology 2015;62:1697–1709)
Clinical Benefit With Docetaxel Plus Fluorouracil and Cisplatin Compared With Cisplatin and Fluorouracil in a Phase III Trial of Advanced Gastric or Gastroesophageal Adenocarcinoma: The V-325 Study Group
Authors: Jaffer A. Ajani, Vladimir M. Moiseyenko, Sergei Tjulandin, Alejandro Majlis, Manuel Constenla, Corrado Boni, Adriano Rodrigues, Miguel Fodor, Yee Chao, Edouard Voznyi, Cindy Marabotti, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2007)

For patients with advanced gastric or gastroesophageal cancer (AGGEC) providing clinical benefit with improved palliation is highly desirable. However, a prospective evaluation of clinical benefit in AGGEC patients has never before been reported in a phase III setting.In a multinational trial (V325), 445 patients were randomly assigned and treated with either docetaxel plus cisplatin and fluorouracil (DCF) or cisplatin and fluorouracil (CF). Clinical benefit was prospectively evaluated in this trial as a secondary end point. The primary measure for clinical benefit analysis was time to definitive worsening by one or more categories of Karnofsky performance status (KPS). Secondary clinical benefit end points included time to 5% definitive weight loss, time to definitive worsening of appetite by one grade, pain-free survival (defined as time to first appearance of pain), and time to first cancer pain-related opioid intake. Clinical benefit assessments were recorded at each clinic visit.Clinical benefit assessments were performed in more than 75% of patients throughout V325. DCF significantly prolonged time to definitive worsening of KPS compared with CF (median, 6.1 v 4.8 months; hazard ratio, 1.38; 95% CI, 1.08 to 1.76; log-rank P = .009). Although time to definitive weight loss and time to definitive worsening of appetite favored DCF, the results were not statistically significant. Pain-free survival and time to first cancer pain-related opioid intake were comparable.To our knowledge, V325 is the first phase III trial to report clinical benefit in AGGEC patients. Clinical benefit was assessed beyond protocol-specific chemotherapy. The addition of D to CF not only significantly improved clinical benefit but also improved quality of life, time to progression, and overall survival compared with CF.
Antiemetic Efficacy of High-Dose Metoclopramide: Randomized Trials with Placebo and Prochlorperazine in Patients with Chemotherapy-Induced Nausea and Vomiting
Authors: Richard J. Gralla, Loretta M. Itri, Sharon E. Pisko, Anna E. Squillante, David P. Kelsen, David W. Braun, Laurie A. Bordin, Thomas J. Braun, Charles W. Young
Journal: New England Journal of Medicine (1981)

In a study of the effectiveness of high intravenous doses of metoclopramide as an antiemetic, 41 patients with advanced cancer who were being treated with cisplatin were entered into two double-blind trials. In the first trial patients were randomly assigned to receive either metoclopramide or placebo, and in the second trial they received either metoclopramide or prochlorperazine. Patients given metoclopramide had significantly fewer episodes of emesis than patients given placebo (medians, 1.0 vs. 10.5; P = 0.001) or prochlorperazine (medians, 1.5 vs. 12.0; P = 0.005). Metoclopramide was superior to placebo and to prochlorperazine in reducing the volume of emesis (P = 0.001 and P = 0.022, respectively) and was more effective than placebo in shortening the duration of nausea (P = 0.042) and vomiting (P = 0.028). Side effects from metoclopramide were minor, with mild sedation frequently observed; one patient had a brief extrapyramidal reaction. We conclude that metoclopramide in high intravenous doses has greater antiemetic activity than placebo or prochlorperazine in patients receiving cisplatin chemotherapy. (N Engl J Med. 1981; 305:905–9.)
GLYCOMICS APPROACH TO STRUCTURE-FUNCTION RELATIONSHIPS OF GLYCOSAMINOGLYCANS
Authors: Ram Sasisekharan, Rahul Raman, Vikas Prabhakar
Journal: Annual Review of Biomedical Engineering (2006)

Extracellular modulation of phenotype is an emerging paradigm in this current postgenomics age of molecular and cell biology. Glycosaminoglycans (GAGs) are primary components of the cell surface and the cell-extracellular matrix (ECM) interface. Advances in the technology to analyze GAGs and in whole-organism genetics have led to a dramatic increase in the known important biological role of these complex polysaccharides. Owing to their ubiquitous distribution at the cell-ECM interface, GAGs interact with numerous proteins and modulate their activity, thus impinging on fundamental biological processes such as cell growth and development. Many recent reviews have captured important aspects of GAG structure and biosynthesis, GAG-protein interactions, and GAG biology. GAG research is currently at a stage where there is a need for an integrated systems or glycomics approach, which involves an integration of all of the above concepts to define their structure-function relationships. Focusing on heparin/heparan (HSGAGs) and chondroitin/dermatan sulfate (CSGAGs), this review highlights the important aspects of GAGs and summarizes these aspects in the context of taking a glycomics approach that integrates the different technologies to define structure-function relationships of GAGs.
Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption
Authors: Michel Azizi, Joël Ménard, Alvine Bissery, Than-Tam Guyenne, Alessandra Bura-Rivière, Sujata Vaidyanathan, Riccardo P Camisasca
Journal: Journal of the American Society of Nephrology (2004)

Interrupting the renin-angiotensin system (RAS) with a usual daily dose of a single-site RAS inhibitor does not achieve complete and long-lasting pharmacologic blockade. Hormonal and BP effects were compared for 48 h after administration of single oral doses of 300 mg (high dose) of the renin inhibitor aliskiren (A300) and 160 mg (standard antihypertensive dose) of the AT1 receptor antagonist valsartan (V160) and their combination each at half dose (A150+V80) in 12 mildly sodium-depleted normotensive individuals. In this double-blind, placebo-controlled, randomized, four-period crossover study, A300 decreased plasma renin activity and angiotensin I and II levels for 48 h, stimulated immunoreactive active renin release more strongly than V160, and decreased urinary aldosterone excretion for a longer duration than V160. In contrast to V160, the A150+V80 combination did not increase plasma angiotensins. The renin and aldosterone effects of the A150+V80 combination were similar to those of A300 and greater than those of V160. When plasma drug concentrations were taken into account, the A150 +V80 combination had a synergistic effect on renin release. The A150+V80 combination lowered BP at least as effectively as either higher dose monotherapy. In conclusion, in mildly sodium-depleted normotensive individuals, the long-lasting effects of aliskiren alone or in combination with valsartan on plasma immunoreactive active renin and urinary aldosterone effects demonstrate strong and prolonged blockade of angiotensin II at the kidney and the adrenal level. Moreover, a renin inhibitor and AT1R antagonist combination may provide synergistic effects on RAS hormone levels.
Diagnosis of autism
Authors: G. Baird
Journal: BMJ (2003)

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Parents want autism to be diagnosed as early as possible, and early intervention may improve long term outcomes. The authors of this review discuss the identification and assessment process for children with autism and autistic spectrum disorder

Autistic spectrum disorders have been the subject of increasing attention over the past few years–from the media, from clinicians, and from the general public. Stories of savants who excel in such skills as calendar calculations and detailed drawings have long been a fascination to public and clinician alike, exemplified in Dustin Hoffman's portrayal of a young man with autism in the film Rainman . Most recently, public anxiety about autism has been raised as a result of reports linking the measles, mumps, and rubella (MMR) vaccine with autism and inflammatory bowel disorder and a rise in the prevalence of autism.1 2 This has resulted in a serious fall in immunisation rates,3 despite the epidemiological evidence of a lack of association,4 and strong reassurance from the Department of Health and the Royal College of Paediatrics and Child Health about the safety of the MMR vaccine. Parents of children with autism continue to express the view that the medical profession does not take their concerns about possible causes of autism seriously. “Miracle cures” for autism–for example, with secretin–have received wide publicity through television and raised enormous hopes before being placed in their proper context by double blind trials that have not confirmed a curative effect. We consulted recent reviews, specialist journals, and recent Medline papers on the diagnosis of autism.

Autism is a behaviourally defined disorder, characterised by qualitative impairments in social communication, social interaction, and social imagination, with a restricted range of interests and often stereotyped repetitive behaviours and mannerisms. Sensory hyposensitivities or hypersensitivities to the environment are common features. …