tbuckley/cabot-search huggingface dataset:
Fluorescence-Based Codetection with Protein Markers Reveals Distinct Cellular Compartments for Altered MicroRNA Expression in Solid Tumors
Authors: Lorenzo F. Sempere, Meir Preis, Todd Yezefski, Haoxu Ouyang, Arief A. Suriawinata, Asli Silahtaroglu, Jose R. Conejo-Garcia, Sakari Kauppinen, Wendy Wells, Murray Korc
Journal: Clinical Cancer Research (2010)

Abstract Purpose: High-throughput profiling experiments have linked altered expression of microRNAs (miRNA) to different types of cancer. Tumor tissues are a heterogeneous mixture of not only cancer cells, but also supportive and reactive tumor microenvironment elements. To clarify the clinical significance of altered miRNA expression in solid tumors, we developed a sensitive fluorescence-based in situ hybridization (ISH) method to visualize miRNA accumulation within individual cells in formalin-fixed, paraffin-embedded tissue specimens. This ISH method was implemented to be compatible with routine clinical immunohistochemical (IHC) assays to enable the detection of miRNAs and protein markers in the same tissue section for colocalization and functional studies. Experimental Design: We used this combined ISH/IHC assay to study a subset of cancer-associated miRNAs, including miRNAs frequently detected at low (miR-34a and miR-126) and high (miR-21 and miR-155) levels, in a panel of breast, colorectal, lung, pancreas, and prostate carcinomas. Results: Despite the distinct histopathologic alterations of each particular cancer type, general trends emerged that pinpointed distinct source cells of altered miRNA expression. Although altered expressions of miR-21 and miR-34a were manifested within cancer cells, those of miR-126 and miR-155 were predominantly confined to endothelial cells and immune cells, respectively. These results suggest a heterogeneous participation of miRNAs in carcinogenesis by intrinsically affecting cancer cell biology or by modulating stromal, vascular, and immune responses. Conclusions: We described a rapid and sensitive multicolor ISH/IHC assay and showed that it could be broadly applied as an investigational tool to better understand the etiologic relevance of altered miRNA expression in cancer. Clin Cancer Res; 16(16); 4246–55. ©2010 AACR.
Do Erythropoietin Receptors on Cancer Cells Explain Unexpected Clinical Findings?
Authors: Michael Henke, Dominik Mattern, Margaret Pepe, Christina Bézay, Christian Weissenberger, Martin Werner, Frank Pajonk
Journal: Journal of Clinical Oncology (2006)

Recent reports suggest that cancer control may worsen if erythropoietin is administered. We investigated whether erythropoietin receptor expression on cancer cells may correlate with this unexpected finding.Cancer tissue from patients with advanced carcinoma of the head and neck (T3, T4, or nodal involvement) and scheduled for radiotherapy was assayed retrospectively for erythropoietin receptor expression by immunohistochemistry. Patients were anemic and randomized to receive epoetin beta (300 U/kg) or placebo under double-blind conditions, given three times weekly starting 10 to 14 days before and continuing throughout radiotherapy. We administered 60 Gy following complete resection or 64 Gy subsequent to microscopically incomplete resection; 70 Gy were given following macroscopically incomplete resection or for definitive radiotherapy alone. We determined if the effect of epoetin beta on locoregional progression-free survival was correlated with the expression of erythropoietin receptors on cancer cells using a Cox proportional hazards regression model.We studied 154 of 157 randomly assigned patients; 104 samples were positive, and 50 were negative for receptor expression. Locoregional progression-free survival was substantially poorer if epoetin beta was administered to patients positive for receptor expression compared with placebo (adjusted relative risk, 2.07; 95% CI, 1.27 to 3.36; P < .01). In contrast, epoetin beta did not impair outcome in receptor-negative patients (adjusted relative risk, 0.94; 95% CI, 0.47 to 1.90; P = .86). The difference in treatment associated relative risks (2.07 v 0.94) was borderline statistically significant (P = .08).Erythropoietin might adversely affect prognosis of head and neck cancer patients if cancer cells express erythropoietin receptors.
VEPEMB in elderly Hodgkin’s lymphoma patients. Results from an Intergruppo Italiano Linfomi (IIL) study
Authors: A. Levis, A.P. Anselmo, A. Ambrosetti, F. Adamo, M. Bertini, E. Cavalieri, P. Gavarotti, A. Genua, M. Liberati, V. Pavone, D. Pietrasanta, M.M. Ricetti, D.R. Scalabrini, F. Salvi, U. Vitolo, E. Angelucci, M. Boccadoro, E. Gallo, F. Mandelli
Journal: Annals of Oncology (2003)
Mouse Models of Cancer
Authors: Dong-Joo Cheon, Sandra Orsulic
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Genetically engineered mouse models have significantly contributed to our understanding of cancer biology. They have proven to be useful in validating gene functions, identifying novel cancer genes and tumor biomarkers, gaining insight into the molecular and cellular mechanisms underlying tumor initiation and multistage processes of tumorigenesis, and providing better clinical models in which to test novel therapeutic strategies. However, mice still have significant limitations in modeling human cancer, including species-specific differences and inaccurate recapitulation of de novo human tumor development. Future challenges in mouse modeling include the generation of clinically relevant mouse models that recapitulate the molecular, cellular, and genomic events of human cancers and clinical response as well as the development of technologies that allow for efficient in vivo imaging and high-throughput screening in mice.
Remarkable Response to Crizotinib in Woman With Anaplastic Lymphoma Kinase–Rearranged Anaplastic Thyroid Carcinoma
Authors: Yann Godbert, Bénédicte Henriques de Figueiredo, Françoise Bonichon, Frédéric Chibon, Isabelle Hostein, Gaëlle Pérot, Camille Dupin, Agnès Daubech, Genevieve Belleannée, Audrey Gros, Antoine Italiano, Isabelle Soubeyran
Journal: Journal of Clinical Oncology (2014)
Diagnosis of diabetes mellitus
Authors: J. S. Soeldner
Journal: JAMA (1979)

<h3>To the Editor.—</h3> In the article by Turkington and Weindling entitled "Insulin Secretion in the Diagnosis of Adult-Onset Diabetes Mellitus" (240:833, 1978), the authors suggest that the demonstration of "insulin deficiency should be essential to establish the diagnosis of diabetes mellitus." Their data are interesting and provocative. However, before accepting their interpretation, it appears that several variables in this study were uncontrolled, suggesting that the interpretation of the study be de-emphasized. From a general point of view, the authors tend to stress insulin deficiency in absolute terms as essential in the diagnosis of diabetes mellitus without correlating this with the degree of glycemia, carbohydrate intolerance, or obesity. Many normal persons with relatively low insulin responses clearly do not have hyperglycemic or diabetic complications. Perhaps the authors' conclusions would be more firm if they employed one of the time-honored insulin-glucose relationships. Information concerning glucose levels or glucose tolerance tests during the
Comparative analyses of CTCF and BORIS occupancies uncover two distinct classes of CTCF binding genomic regions
Authors: Elena M. Pugacheva, Samuel Rivero-Hinojosa, Celso A. Espinoza, Claudia Fabiola Méndez-Catalá, Sungyun Kang, Teruhiko Suzuki, Natsuki Kosaka-Suzuki, Susan Robinson, Vijayaraj Nagarajan, Zhen Ye, Abdelhalim Boukaba, John E. J. Rasko, Alexander V. Strunnikov, Dmitri Loukinov, Bing Ren, Victor V. Lobanenkov
Journal: Genome biology (2015)

CTCF and BORIS (CTCFL), two paralogous mammalian proteins sharing nearly identical DNA binding domains, are thought to function in a mutually exclusive manner in DNA binding and transcriptional regulation. Here we show that these two proteins co-occupy a specific subset of regulatory elements consisting of clustered CTCF binding motifs (termed 2xCTSes). BORIS occupancy at 2xCTSes is largely invariant in BORIS-positive cancer cells, with the genomic pattern recapitulating the germline-specific BORIS binding to chromatin. In contrast to the single-motif CTCF target sites (1xCTSes), the 2xCTS elements are preferentially found at active promoters and enhancers, both in cancer and germ cells. 2xCTSes are also enriched in genomic regions that escape histone to protamine replacement in human and mouse sperm. Depletion of the BORIS gene leads to altered transcription of a large number of genes and the differentiation of K562 cells, while the ectopic expression of this CTCF paralog leads to specific changes in transcription in MCF7 cells. We discover two functionally and structurally different classes of CTCF binding regions, 2xCTSes and 1xCTSes, revealed by their predisposition to bind BORIS. We propose that 2xCTSes play key roles in the transcriptional program of cancer and germ cells.
Growth of Engineered Human Myocardium With Mechanical Loading and Vascular Coculture
Authors: Nathaniel L. Tulloch, Veronica Muskheli, Maria V. Razumova, F. Steven Korte, Michael Regnier, Kip D. Hauch, Lil Pabon, Hans Reinecke, Charles E. Murry
Journal: Circulation Research (2011)

Rationale: The developing heart requires both mechanical load and vascularization to reach its proper size, yet the regulation of human heart growth by these processes is poorly understood. Objective: We seek to elucidate the responses of immature human myocardium to mechanical load and vascularization using tissue engineering approaches. Methods and Results: Using human embryonic stem cell and human induced pluripotent stem cell–derived cardiomyocytes in a 3-dimensional collagen matrix, we show that uniaxial mechanical stress conditioning promotes 2-fold increases in cardiomyocyte and matrix fiber alignment and enhances myofibrillogenesis and sarcomeric banding. Furthermore, cyclic stress conditioning markedly increases cardiomyocyte hypertrophy (2.2-fold) and proliferation rates (21%) versus unconditioned constructs. Addition of endothelial cells enhances cardiomyocyte proliferation under all stress conditions (14% to 19%), and addition of stromal supporting cells enhances formation of vessel-like structures by ≈10-fold. Furthermore, these optimized human cardiac tissue constructs generate Starling curves, increasing their active force in response to increased resting length. When transplanted onto hearts of athymic rats, the human myocardium survives and forms grafts closely apposed to host myocardium. The grafts contain human microvessels that are perfused by the host coronary circulation. Conclusions: Our results indicate that both mechanical load and vascular cell coculture control cardiomyocyte proliferation, and that mechanical load further controls the hypertrophy and architecture of engineered human myocardium. Such constructs may be useful for studying human cardiac development as well as for regenerative therapy.
Changes in plasma enzyme activities in professional racing cyclists.
Authors: P Mena, M Maynar, J E Campillo
Journal: British Journal of Sports Medicine (1996)

OBJECTIVE: To reports changes in plasma levels in professional racing cyclists. METHODS: Plasma levels of the intracellular enzymes aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, lactate dehydrogenase, and alkaline phosphatase were measured resting and after exercise in professional cyclists participating in two road races: Vuelta Ciclista a Valencia (800 km, beginning of the cyclist season), and the top rank race Vuelta a España (2700 km, at the end of cyclist season). RESULTS: A significant increase in plasma aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase was observed at the end of the race over the corresponding paired start values (P &lt; 0.05). The increase in plasma lactate dehydrogenase after the race was only statistically significant (P &lt; 0.05) in the Vuelta a España. The longer the duration of the cycle tour race, the greater were the increases in aspartate aminotransferase and alanine aminotransferase levels. The high levels returned to their start values during the overnight resting period. CONCLUSIONS: The presence of these enzymes in the blood is probably due to mechanically damaged muscle cells leaking their contents into the interstitial fluid.
Clinical relevance of melanoma micrometastases (&lt;0.1 mm) in sentinel nodes: are these nodes to be considered negative?
Authors: A.C.J. van Akkooi, J.H.W. de Wilt, C. Verhoef, P.I.M. Schmitz, A.N. van Geel, A.M.M. Eggermont, M. Kliffen
Journal: Annals of Oncology (2006)
How will the new genetics work?
Authors: J Murray
Journal: BMJ (1983)

calculating the receiver operating character- istic for each sensitivity-specificity pair.'2When analysed in this way 10 clinical features emerged as having testing ability; they are listed in the table in order of their value.Receiver operating characteristics of clinical indicators for brain computed tomography in patients with recent onset dementia Sensitivity Specificity Clinical indicator (0,,) (°,) d' Focal neurological signs 42 88 097 Papilloedema
Acetaminophen Use and Risk of Asthma, Rhinoconjunctivitis, and Eczema in Adolescents
Authors: Richard W Beasley, Tadd O Clayton, Julian Crane, Christopher K W Lai, Stephen R Montefort, Erika von Mutius, Alistair W Stewart
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

There is epidemiological evidence that the use of acetaminophen may increase the risk of developing asthma.To investigate the risk of asthma and other allergic disorders associated with the current use of acetaminophen in 13- to 14-year-old children in different populations worldwide.As part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three, 13- to 14-year-old children completed written and video questionnaires obtaining data on current symptoms of asthma, rhinoconjunctivitis, and eczema, and a written environmental questionnaire obtaining data on putative risk factors, including acetaminophen use in the past 12 months.The primary outcome measure was the odds ratio (OR) of current asthma symptoms associated with acetaminophen use calculated by logistic regression. A total of 322,959 adolescent children from 113 centers in 50 countries participated. In the multivariate analyses the recent use of acetaminophen was associated with an exposure-dependent increased risk of current asthma symptoms (OR, 1.43 [95% confidence interval, 1.33-1.53] and 2.51 [95% confidence interval, 2.33-2.70] for medium and high versus no use, respectively). Acetaminophen use was also associated with an exposure-dependent increased risk of current symptoms of rhinoconjunctivitis and eczema.Acetaminophen use may represent an important risk factor for the development and/or maintenance of asthma, rhinoconjunctivitis, and eczema in adolescent children.
Differential Mechanisms of Acquired Resistance to Insulin-like Growth Factor-I Receptor Antibody Therapy or to a Small-Molecule Inhibitor, BMS-754807, in a Human Rhabdomyosarcoma Model
Authors: Fei Huang, Warren Hurlburt, Ann Greer, Karen A. Reeves, Stephen Hillerman, Han Chang, Joseph Fargnoli, Friedrich Graf Finckenstein, Marco M. Gottardis, Joan M. Carboni
Journal: Cancer Research (2010)

Abstract Agents targeting insulin-like growth factor-I receptor (IGF-IR), including antibodies and small-molecule inhibitors, are currently in clinical development for the treatment of cancers including sarcoma. However, development of resistance is a common phenomenon resulting in failures of anticancer therapies. In light of this problem, we developed two resistant models from the rhabdomyosarcoma cell line Rh41: Rh41-807R, with acquired resistance to BMS-754807, a small-molecule dual-kinase inhibitor targeting IGF-IR and insulin receptor (IR), and Rh41-MAB391R, with resistance to MAB391, an IGF-IR–blocking antibody. In addition, tumor xenograft models were established from Rh41 and Rh41-807R cell lines. Gene expression and DNA copy number analyses of these models revealed shared as well as unique acquired resistance mechanisms for the two types of IGF-IR inhibitors. Each resistant model used different signaling pathways as a mechanism for proliferation. Platelet-derived growth factor receptor α (PDGFRα) was amplified, overexpressed, and constitutively activated in Rh41-807R cells and tumors. Knockdown of PDGFRα by small interfering RNA in Rh41-807R resensitized the cells to BMS-754807. Synergistic activities were observed when BMS-754807 was combined with PDGFRα inhibitors in the Rh41-807R model in vitro. In contrast, AXL expression was highly elevated in Rh41-MAB391R but downregulated in Rh41-807R. Notably, BMS-754807 was active in Rh41-MAB391R cells and able to overcome resistance to MAB391, but MAB391 was not active in Rh41-807R cells, suggesting potentially broader clinical activity of BMS-754807. This is the first study to define and compare acquired resistance mechanisms for IGF-IR–targeted therapies. It provides insights into the differential acquired resistance mechanisms for IGF-IR/IR small-molecule inhibitor versus anti–IGF-IR antibody. Cancer Res; 70(18); 7221–31. ©2010 AACR.
Increased Positive Versus Negative Affective Perception and Memory in Healthy Volunteers Following Selective Serotonin and Norepinephrine Reuptake Inhibition
Authors: Catherine J. Harmer, Nicholas C. Shelley, Philip J. Cowen, Guy M. Goodwin
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Antidepressants that inhibit the reuptake of serotonin (SSRIs) or norepinephrine (SNRIs) are effective in the treatment of disorders such as depression and anxiety. Cognitive psychological theories emphasize the importance of correcting negative biases of information processing in the nonpharmacological treatment of these disorders, but it is not known whether antidepressant drugs can directly modulate the neural processing of affective information. The present study therefore assessed the actions of repeated antidepressant administration on perception and memory for positive and negative emotional information in healthy volunteers. METHOD: Forty-two male and female volunteers were randomly assigned to 7 days of double-blind intervention with the SSRI citalopram (20 mg/day), the SNRI reboxetine (8 mg/day), or placebo. On the final day, facial expression recognition, emotion-potentiated startle response, and memory for affect-laden words were assessed. Questionnaires monitoring mood, hostility, and anxiety were given before and after treatment. RESULTS: In the facial expression recognition task, citalopram and reboxetine reduced the identification of the negative facial expressions of anger and fear. Citalopram also abolished the increased startle response found in the context of negative affective images. Both antidepressants increased the relative recall of positive (versus negative) emotional material. These changes in emotional processing occurred in the absence of significant differences in ratings of mood and anxiety. However, reboxetine decreased subjective ratings of hostility and elevated energy. CONCLUSIONS: Short-term administration of two different antidepressant types had similar effects on emotion-related tasks in healthy volunteers, reducing the processing of negative relative to positive emotional material. Such effects of antidepressants may ameliorate the negative biases in information processing that characterize mood and anxiety disorders. They also suggest a mechanism of action potentially compatible with cognitive theories of anxiety and depression.
Impact of Valve Prosthesis-Patient Mismatch on Short-Term Mortality After Aortic Valve Replacement
Authors: Claudia Blais, Jean G. Dumesnil, Richard Baillot, Serge Simard, Daniel Doyle, Philippe Pibarot
Journal: Circulation (2003)

Background— The prosthesis used for aortic valve replacement (AVR) can be too small in relation to body size, thus causing valve prosthesis-patient mismatch (PPM) and abnormally high transvalvular pressure gradients. This study examined if there is a relation between PPM and short-term mortality after operation. Methods and Results— The indexed valve effective orifice area (EOA) was estimated for each type and size of prosthesis being implanted in 1266 consecutive patients and used to define PPM as not clinically significant if &gt;0.85 cm 2 /m 2 , as moderate if &gt;0.65 cm 2 /m 2 and ≤0.85 cm 2 /m 2 , and as severe if ≤0.65 cm 2 /m 2 ; it was correlated with 30-day mortality and compared with other relevant variables. Moderate or severe PPM was present in 38% of patients. Thirty-day mortality was 4.6% (58/1266 patients) and the strongest independent predictors in multivariate analysis were left ventricular ejection fraction &lt;40% ( P =0.007), infectious endocarditis ( P =0.002), emergent/salvage operation ( P =0.002), cardiopulmonary bypass time &gt;120 minutes ( P =0.001), and PPM ( P =0.003). Relative risk of mortality was increased 2.1-fold (95% confidence interval, 1.2 to 3.7) in patients with moderate PPM and 11.4-fold (4.4 to 29.5) in those with severe PPM. Moreover, risk of mortality for every category of PPM was higher in patients with a left ventricular ejection fraction &lt;40% as compared with ≥40% (nonsignificant PPM, 2.7 versus 1.0; moderate PPM, 7.1 versus 1.8; severe PPM, 77.1 versus 11.3). Conclusion— PPM is a strong and independent predictor of short-term mortality among patients undergoing AVR, and its impact is related both to its degree of severity and the status of left ventricular function. In contrast to other risk factors, moderate-severe PPM can be largely avoided with the use of a prospective strategy at the time of operation.
Functional Role of CLIC1 Ion Channel in Glioblastoma-Derived Stem/Progenitor Cells
Authors: Matteo Setti, Nicoletta Savalli, Daniela Osti, Cristina Richichi, Marina Angelini, Paola Brescia, Lorenzo Fornasari, Maria Stella Carro, Michele Mazzanti, Giuliana Pelicci
Journal: JNCI Journal of the National Cancer Institute (2013)

Chloride channels are physiologically involved in cell division and motility. Chloride intracellular channel 1 (CLIC1) is overexpressed in a variety of human solid tumors compared with normal tissues, suggesting a potential involvement of CLIC1 in the regulation of tumorigenesis. This led us to investigate the role of CLIC1 in gliomagenesis. We used the neurosphere system to isolate stem/progenitor cells from human glioblastomas (GBMs). CLIC1 targeting in GBM neurospheres was achieved by both lentiviral-mediated short-hairpin RNA transduction and CLIC1 antibody treatment, and its effect on stem-like properties was analyzed in vitro by proliferation and clonogenic assays and in vivo by orthotopic injection in immunocompromised mice. Channel activity was studied by perforated patch clamp technique. Differences in expression were analyzed by analysis of variance with Tamhane's multiple comparison test. Kaplan–Meier analyses and log-rank test were used to assess survival. All statistical tests were two-sided. CLIC1 was statistically significantly overexpressed in GBMs compared with normal brain tissues ( P < .001) with a better survival of patients with CLIC1 low-expressing tumors (CLIC1 low vs CLIC1 high survival: χ 2 = 74.35; degrees of freedom = 1; log-rank P < .001). CLIC1 was variably expressed in patient-derived GBM neurospheres and was found enriched in the stem/progenitor compartment. CLIC1 silencing reduced proliferative ( P < .01), clonogenic ( P < .01), and tumorigenic capacity ( P < .05) of stem/progenitor cells. The reduction of CLIC1 chloride currents with a specific CLIC1 antibody mirrored the biological effects of CLIC1 silencing in GBM patient–derived neurospheres. Reduced gliomagenesis after CLIC1 targeting in tumoral stem/progenitor cells and the finding that CLIC1 expression is inversely associated with patient survival suggest CLIC1 as a potential target and prognostic biomarker.