tbuckley/cabot-search huggingface dataset:
<i>BRAF</i>Mutations in Hairy-Cell Leukemia
Authors: Enrico Tiacci, Vladimir Trifonov, Gianluca Schiavoni, Antony Holmes, Wolfgang Kern, Maria Paola Martelli, Alessandra Pucciarini, Barbara Bigerna, Roberta Pacini, Victoria A. Wells, Paolo Sportoletti, Valentina Pettirossi, Roberta Mannucci, Oliver Elliott, Arcangelo Liso, Achille Ambrosetti, Alessandro Pulsoni, Francesco Forconi, Livio Trentin, Gianpietro Semenzato, Giorgio Inghirami, Monia Capponi, Francesco Di Raimondo, Caterina Patti, Luca Arcaini, Pellegrino Musto, Stefano Pileri, Claudia Haferlach, Susanne Schnittger, Giovanni Pizzolo, Robin Foà, Laurent Farinelli, Torsten Haferlach, Laura Pasqualucci, Raul Rabadan, Brunangelo Falini
Journal: New England Journal of Medicine (2011)

Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure.We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL.Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).
Rat lung fibroblast collagen metabolism in bleomycin-induced pulmonary fibrosis.
Authors: S H Phan, J Varani, D Smith
Journal: Journal of Clinical Investigation (1985)

Endotracheal bleomycin administration in rats and other animal species causes rapid development of pulmonary fibrosis, characterized by increased lung collagen synthesis and deposition. To clarify the mechanism, lung fibroblasts from bleomycin-treated rats (BRF) were isolated and maintained in tissue culture. They were then compared with those from normal untreated control animals, with respect to several key parameters of collagen metabolism. BRF synthesized collagen at a rate 35-82% above normal rat lung fibroblasts (NRF). This difference did not appear to be due to the selection of a clone by the subculture process. Furthermore, analysis of newly synthesized collagen type composition, revealed a significantly lower ratio of type III to type I collagen. Noncollagenous protein synthesis, however, was not significantly different from normal. Collagenase production and growth rate were also unaffected. BRF, however, was morphologically indistinguishable from NRF, even at the ultrastructural level. Upon further bleomycin (1 microgram/ml) exposure in vitro, BRF could be further stimulated to synthesize collagen at 82% above the rate for untreated BRF. This is comparable to the 90% increase in NRF treated in vitro (compared with untreated NRF). These results would favor the conclusion that bleomycin induces pulmonary fibrosis, by causing directly and/or indirectly lung fibroblasts (or a certain line of lung fibroblasts) to synthesize collagen at a higher rate without any associated increase in growth rate. The data, however, do not rule out the possibility that the fibroblast isolation procedure has selected for a certain population of fibroblasts that may not be typical of the in vivo situation.
Contrasting Hypoxic Effects on Breast Cancer Stem Cell Hierarchy Is Dependent on ER-α Status
Authors: Hannah Harrison, Lynsey Rogerson, Hannah J. Gregson, Keith R. Brennan, Robert B. Clarke, Göran Landberg
Journal: Cancer Research (2012)

Tumor hypoxia is often linked to decreased survival in patients with breast cancer and current therapeutic strategies aim to target the hypoxic response. One way in which this is done is by blocking hypoxia-induced angiogenesis. Antiangiogenic therapies show some therapeutic potential with increased disease-free survival, but these initial promising results are short lived and followed by tumor progression. We hypothesized that this may be due to altered cancer stem cell (CSC) activity resulting from increased tumor hypoxia. We studied the effects of hypoxia on CSC activity, using in vitro mammosphere and holoclone assays as well as in vivo limiting dilution experiments, in 13 patient-derived samples and four cell lines. There was a HIF-1α-dependent CSC increase in ER-α-positive cancers following hypoxic exposure, which was blocked by inhibition of estrogen and Notch signaling. A contrasting decrease in CSC was seen in ER-α-negative cancers. We next developed a xenograft model of cell lines and patient-derived samples to assess the hypoxic CSC response. Varying sizes of xenografts were collected and analyzed for HIF1-α expression and CSC. The same ER-α-dependent contrasting hypoxic-CSC response was seen validating the initial observation. These data suggest that ER-α-positive and negative breast cancer subtypes respond differently to hypoxia and, as a consequence, antiangiogenic therapies will not be suitable for both subgroups.
Press Release: High-Dose Chemotherapy Not Superior to Conventional Chemotherapy in High-Risk Breast Cancer Patients
Authors: S. L. Zielinski
Journal: JNCI Journal of the National Cancer Institute (2004)

An often-cited barrier to enrollment in cancer clinical trials is payer reimbursement.Gross et al. (p.1063) examined if state mandates ensuring coverage of routine medical care costs of cancer trial participants increased patient enrollment rates for National Cancer Institute-sponsored phase II and cooperative group phase III trials between 1996 and 2001.They compared enrollment of participants in four states that had enacted coverage policies in 1999 with enrollment in states without policies.After the state mandates were enacted in 1999, the authors found that phase II trial enrollment increased at a greater rate in states with coverage policies compared with states without policies.However, phase III trial enrollment increased at a similar rate in all states, suggesting that coverage mandates were not associated with an increase in phase III trial enrollment.In an editorial, Hillner (p.1048) addresses the effect of state mandates that cover patient care costs of clinical trial participation on trial enrollment.He discusses the issue of cost as a barrier to enrollment as well as other potential enrollment barriers.
Ultrasound-Targeted Microbubble Destruction Can Repeatedly Direct Highly Specific Plasmid Expression to the Heart
Authors: Raffi Bekeredjian, Shuyuan Chen, Peter A. Frenkel, Paul A. Grayburn, Ralph V. Shohet
Journal: Circulation (2003)

Noninvasive, tissue-specific delivery of therapeutic agents would be a valuable clinical tool. We have previously shown that ultrasound-targeted microbubble destruction can direct expression of an adenoviral reporter to the heart. The present study shows that this method can be applied to selectively deliver plasmid vectors to the heart.We used albumin and lipid microbubbles containing plasmids with a luciferase transgene to target the heart in rats. After 4 days, organs were harvested and analyzed for reporter gene expression. In a second set of experiments, the hearts of rats treated with plasmids were harvested at various time points during a 4-week period. Both luciferase activity and mRNA concentrations were measured. Luciferase transfection with plasmids showed highly specific gene expression in the heart, with hardly any activity in control organs. Time course evaluation showed high transgene expression in the first 4 days, with a rapid decline thereafter. Repeated treatment produced a second peak of transgene expression with similar decay.Ultrasound-mediated destruction of microbubbles directs plasmid transgene expression to the heart with much greater specificity than viral vectors and can be regulated by repeated treatments. This noninvasive technique is a promising method for cardiac gene therapy.
Reperfusion injury: laboratory phenomenon or clinical reality?
Authors: K. A A Fox
Journal: Cardiovascular Research (1992)

Journal Article Reperfusion injury: laboratory phenomenon or clinical reality? Get access Keith A A Fox Keith A A Fox Cardiovascular Research Unit, Hugh Robson Building, George Square, Edinburgh EH8 9XF, United Kingdom. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 26, Issue 7, July 1992, Pages 656–659, https://doi.org/10.1093/cvr/26.7.656 Published: 01 July 1992
Förster Transfer Recovery Reveals That Phospholamban Exchanges Slowly From Pentamers but Rapidly From the SERCA Regulatory Complex
Authors: Seth L. Robia, Kenneth S. Campbell, Eileen M. Kelly, Zhanjia Hou, Deborah L. Winters, David D. Thomas
Journal: Circulation Research (2007)

Phospholamban (PLB) or the sarcoplasmic reticulum Ca 2+ –ATPase (SERCA) were fused to cyan fluorescent protein (CFP) and coexpressed with PLB fused to yellow fluorescent protein (YFP). The expressed fluorescently tagged proteins were imaged using epifluorescence and total internal reflection fluorescence microscopy. YFP fluorescence was selectively bleached by a focused laser beam. CFP fluorescence at the targeted site increased after YFP photobleaching, indicating fluorescence resonance energy transfer between CFP-SERCA/CFP-PLB and YFP-PLB. The increased donor fluorescence relaxed back toward baseline as a result of donor diffusion and exchange of bleached YFP-PLB for unbleached YFP-PLB, which restored fluorescence resonance energy transfer. Requenching of CFP donors, termed Förster transfer recovery (FTR), was quantified as an index of the rate of PLB subunit exchange from the PLB:SERCA and PLB:PLB membrane complexes. PLB subunit exchange from the PLB:SERCA regulatory complex was rapid, showing diffusion-limited FTR (τ=1.4 second). Conversely, PLB:PLB oligomeric complexes were found to be stable on a much longer time scale. Despite free lateral diffusion in the membrane, they showed no FTR over 80 seconds. Mutation of PLB position 40 from isoleucine to alanine (I40A-PLB) did not abolish PLB:PLB energy transfer, but destabilization of the PLB:PLB complex was apparent from an increased FTR rate (τ=8.4 seconds). Oligomers of I40A-PLB were stabilized by oxidative crosslinking of transmembrane cysteines with diamide. We conclude that PLB exchanges rapidly from its regulatory complex with the SERCA pump, whereas subunit exchange from the PLB oligomeric complex is slow and does not occur on the time scale of the cardiac cycle.
Bone Mass and Microarchitecture in CKD Patients with Fracture
Authors: Thomas L. Nickolas, Emily Stein, Adi Cohen, Valerie Thomas, Ronald B. Staron, Donald J. McMahon, Mary B. Leonard, Elizabeth Shane
Journal: Journal of the American Society of Nephrology (2010)

Patients with predialysis chronic kidney disease (CKD) have increased risk for fracture, but the structural mechanisms underlying this increased skeletal fragility are unknown. We measured areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry at the spine, hip, and radius, and we measured volumetric BMD (vBMD), geometry, and microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the radius and tibia in patients with CKD: 32 with fracture and 59 without fracture. Patients with fracture had lower aBMD at the spine, total hip, femoral neck, and the ultradistal radius, the last having the strongest association with fracture. By HR-pQCT of the radius, patients with fracture had lower cortical area and thickness, total and trabecular vBMD, and trabecular number and greater trabecular separation and network heterogeneity. At the tibia, patients with fracture had significantly lower cortical area, thickness, and total and cortical density. Total vBMD at both radius and tibia most strongly associated with fracture. By receiver operator characteristic curve analysis, patients with longer duration of CKD had area under the curve of >0.75 for aBMD at both hip sites and the ultradistal radius, vBMD and geometry at the radius and tibia, and microarchitecture at the tibia. In summary, patients with predialysis CKD and fractures have lower aBMD by dual-energy x-ray absorptiometry and lower vBMD, thinner cortices, and trabecular loss by HR-pQCT. These density and structural differences may underlie the increased susceptibility to fracture among patients with CKD.
Acute Hypoglycemia Impairs Nonverbal Intelligence
Authors: Roderick E. Warren, Kate V. Allen, Andrew J. Sommerfield, Ian J. Deary, Brian M. Frier
Journal: Diabetes Care (2004)

Acute hypoglycemia causes a progressive, reversible deterioration in cognitive function that becomes detectable at blood glucose concentrations below ∼3.0–3.4 mmol/l (1). In an earlier study in nondiabetic subjects, we reported that several facets of attention deteriorated significantly at an arterialized blood glucose level of 2.6 mmol/l (2). However, performance on Raven’s Progressive Matrices (RPM) was not significantly impaired at either 20 min or completion of the test (with no time limit). This was unexpected, because, previously, various domains of cognitive function had consistently been impaired at this level of hypoglycemia (1). Additionally, the RPM is acknowledged as being among the best indicators of general fluid intelligence (3) and has a substantial correlation with working memory (4), which is exquisitely sensitive to hypoglycemia (5).

Hypoglycemia disrupts performance on different cognitive function tests to a variable degree, leading to speculation that different mental functions vary …
Computational comparison of two mouse draft genomes and the human golden path
Authors: Zhenyu Xuan, Jinhua Wang, Michael Q Zhang
Journal: Genome biology (2002)

The availability of both mouse and human draft genomes has marked the beginning of a new era of comparative mammalian genomics. The two available mouse genome assemblies, from the public mouse genome sequencing consortium and Celera Genomics, were obtained using different clone libraries and different assembly methods. We present here a critical comparison of the two latest mouse genome assemblies. The utility of the combined genomes is further demonstrated by comparing them with the human 'golden path' and through a subsequent analysis of a resulting conserved sequence element (CSE) database, which allows us to identify over 6,000 potential novel genes and to derive independent estimates of the number of human protein-coding genes. The Celera and public mouse assemblies differ in about 10% of the mouse genome. Each assembly has advantages over the other: Celera has higher accuracy in base-pairs and overall higher coverage of the genome; the public assembly, however, has higher sequence quality in some newly finished bacterial artifical chromosome clone (BAC) regions and the data are freely accessible. Perhaps most important, by combining both assemblies, we can get a better annotation of the human genome; in particular, we can obtain the most complete set of CSEs, one third of which are related to known genes and some others are related to other functional genomic regions. More than half the CSEs are of unknown function. From the CSEs, we estimate the total number of human protein-coding genes to be about 40,000. This searchable publicly available online CSEdb will expedite new discoveries through comparative genomics.
Immunologic Human Renal Allograft Injury Associates with an Altered IL-10/TNF-α Expression Ratio in Regulatory B Cells
Authors: Aravind Cherukuri, David M. Rothstein, Brendan Clark, Clive R. Carter, Adam Davison, Maria Hernandez-Fuentes, Eric Hewitt, Alan D. Salama, Richard J. Baker
Journal: Journal of the American Society of Nephrology (2014)

Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24hiCD38hi transitional B cells (TrBs), CD24hiCD27+ memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. Whereas neutralization of IL-10 significantly inhibited TrB-mediated suppression of autologous Th1 cytokine expression, blocking TNF-α increased the suppressive capacity of both memory and naïve B-cell subsets. Thus, the ratio of IL-10/TNF-α expression, a measure of cytokine polarization, may be a better indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. In summary, these results indicate that B cell–mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.
Randomized Trial of a Telephone-Based Weight Loss Intervention in Postmenopausal Women With Breast Cancer Receiving Letrozole: The LISA Trial
Authors: Pamela J. Goodwin, Roanne J. Segal, Michael Vallis, Jennifer A. Ligibel, Gregory R. Pond, André Robidoux, George L. Blackburn, Brian Findlay, Julie R. Gralow, Som Mukherjee, Mark Levine, Kathleen I. Pritchard
Journal: Journal of Clinical Oncology (2014)

Obesity is associated with poor outcomes in women with operable breast cancer. Lifestyle interventions (LIs) that help women reduce their weight may improve outcomes.We conducted a multicenter randomized trial comparing mail-based delivery of general health information alone or combined with a 24-month standardized, telephone-based LI that included diet (500 to 1,000 kcal per day deficit) and physical activity (150 to 200 minutes of moderate-intensity physical activity per week) goals to achieve weight loss (up to 10%). Women receiving adjuvant letrozole for T1-3N0-3M0 breast cancer with a body mass index (BMI) ≥ 24 kg/m(2) were eligible. Weight was measured in the clinic, and self-report physical activity, quality-of-life (QOL), and diet questionnaires were completed. The primary outcome was disease-free survival. Accrual was terminated at 338 of 2,150 planned patients because of loss of funding.Mean weight loss was significantly (P < .001) greater in the LI arm versus the comparison arm (4.3 v 0.6 kg or 5.3% v 0.7% at 6 months and 3.1 v 0.3 kg or 3.6% v 0.4% at 24 months) and occurred consistently across strata (BMI 24 to < 30 v ≥ 30 kg/m(2); prior v no prior adjuvant chemotherapy). Weight loss was greatest in those with higher baseline levels of moderate-intensity physical activity or improvement in QOL. Hospitalization rates and medical events were similar.A telephone-based LI led to significant weight loss that was still evident at 24 months, without adverse effects on QOL, hospitalizations, or medical events. Adequately powered randomized trials with cancer end points are needed.
Increased endothelin and endothelin receptor mRNA expression in polycystic kidneys of cpk mice.
Authors: T Nakamura, I Ebihara, M Fukui, S Osada, Y Tomino, T Masaki, K Goto, Y Furuichi, H Koide
Journal: Journal of the American Society of Nephrology (1993)

The renal mRNA levels of endothelin (ET)-1 and ET-3 and for ET receptors A and B were measured in the cystic kidneys of cpk/cpk mice at 1, 2, and 3 wk of age. At 1 wk of age, renal ET-1 mRNA was 3.2-fold greater in cystic mice than in controls and continued to increase with the progression of cyst formation to reach 10.4-fold more than controls at 3 wk. ET-3 mRNA levels did not differ between cystic and control mice. Renal ETA and ETB receptor mRNA increased gradually in cystic mice with the progression of their cysts, reaching 4.2- and 6.3-fold increases over controls, respectively, at 3 wk. Proliferating cell nuclear antigen mRNA expression was also examined, and proliferating cell nuclear antigen mRNA levels were found to be significantly increased in the kidneys of cystic mice compared with controls: 2. 1-fold at 1 wk, 4.5-fold at 2 wk, and 7.8-fold at 3 wk. The mRNA levels for transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha) in the kidneys of cystic mice were also examined and were found to be increased progressively with age (TGF-beta, 2.1-fold at 1 wk, 4.2-fold at 2 wk, and 6.2-fold at 3 wk; TNF-alpha, 2.2-fold at 1 wk, 3.8-fold at 2 wk, and 5.4-fold at 3 wk).(ABSTRACT TRUNCATED AT 250 WORDS)
Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis.
Authors: N K Banda, J Bernier, D K Kurahara, R Kurrle, N Haigwood, R P Sekaly, T H Finkel
Journal: The Journal of Experimental Medicine (1992)

During human immunodeficiency virus (HIV) infection there is a profound and selective decrease in the CD4+ population of T lymphocytes. The mechanism of this depletion is not understood, as only a small fraction of all CD4+ cells appear to be productively infected with HIV-1 in seropositive individuals. In the present study, crosslinking of bound gp120 on human CD4+ T cells followed by signaling through the T cell receptor for antigen was found to result in activation-dependent cell death by a form of cell suicide termed apoptosis, or programmed cell death. The data indicate that even picomolar concentrations of gp120 prime T cells for activation-induced cell death, suggesting a mechanism for CD4+ T cell depletion in acquired immune deficiency syndrome (AIDS), particularly in the face of concurrent infection and antigenic challenge with other organisms. These results also provide an explanation for the enhancement of infection by certain antibodies against HIV, and for the paradox that HIV appears to cause AIDS after the onset of antiviral immunity.
Distinct Epidemiology and Clinical Consequence of Classic Versus Rare EGFR Mutations in Lung Adenocarcinoma
Authors: Zoltan Lohinai, Mir Alireza Hoda, Katalin Fabian, Gyula Ostoros, Erzsebet Raso, Tamas Barbai, Jozsef Timar, Ilona Kovalszky, Mihaly Cserepes, Anita Rozsas, Viktoria Laszlo, Michael Grusch, Walter Berger, Walter Klepetko, Judit Moldvay, Balazs Dome, Balazs Hegedus
Journal: Journal of Thoracic Oncology (2015)