tbuckley/cabot-search huggingface dataset:
microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells
Authors: Antoine Marcais, Rory Blevins, Johannes Graumann, Amelie Feytout, Gopuraja Dharmalingam, Thomas Carroll, Inês F. Amado, Ludovica Bruno, Keunwook Lee, Thierry Walzer, Matthias Mann, Antonio A. Freitas, Mark Boothby, Amanda G. Fisher, Matthias Merkenschlager
Journal: The Journal of Experimental Medicine (2014)

T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state of anergy. Here, we ask whether microRNAs affect the interpretation of TCR signaling. We find that Dicer-deficient CD4 T cells fail to correctly discriminate between activating and anergy-inducing stimuli and produce IL-2 in the absence of co-stimulation. Excess IL-2 production by Dicer-deficient CD4 T cells was sufficient to override anergy induction in WT T cells and to restore inducible Foxp3 expression in Il2-deficient CD4 T cells. Phosphorylation of Akt on S473 and of S6 ribosomal protein was increased and sustained in Dicer-deficient CD4 T cells, indicating elevated mTOR activity. The mTOR components Mtor and Rictor were posttranscriptionally deregulated, and the microRNAs Let-7 and miR-16 targeted the Mtor and Rictor mRNAs. Remarkably, returning Mtor and Rictor to normal levels by deleting one allele of Mtor and one allele of Rictor was sufficient to reduce Akt S473 phosphorylation and to reduce co-stimulation–independent IL-2 production in Dicer-deficient CD4 T cells. These results show that microRNAs regulate the expression of mTOR components in T cells, and that this regulation is critical for the modulation of mTOR activity. Hence, microRNAs contribute to the discrimination between T cell activation and anergy.
On demand Gamma-Knife strategy can be safely combined with BRAF inhibitors for the treatment of melanoma brain metastases
Authors: C. Gaudy-Marqueste, R. Carron, C. Delsanti, A. Loundou, S. Monestier, E. Archier, M.A. Richard, J. Regis, J.J. Grob
Journal: Annals of Oncology (2014)
Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures
Authors: Xuan Huang, Cindy H Chau, William D Figg
Journal: Journal of Hematology & Oncology (2012)

Abstract Men with metastatic castration-resistant prostate cancer (mCRPC) carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.
High Complete Response in Advanced Nasopharyngeal Carcinoma With Bleomycin, Epirubicin, and Cisplatin Before Radiotherapy
Authors: M. Bachouchi, E. Cvitkovic, N. Azli, J. Gasmi, H. Cortes-Funes, H. Boussen, M. Rahal, C. Kalifa, G. Schwaab, F. Eschwege, P. Wibault, J. P. Armand
Journal: JNCI Journal of the National Cancer Institute (1990)

Undifferentiated carcinoma of nasopharyngeal type (UCNT) is a geographically endemic, Epstein-Barr virus-related carcinoma of epidermoid origin with reported 5-year survival rates of 15%-40% when treated with radiotherapy alone. Although UCNT can be well controlled locally by radiation therapy, in advanced nodal stage N3 [International Union Against Cancer-American Joint Committee on Cancer (UICC-AJCC, 1987)] the survival rate is below 20%, primarily because of metastatic spread in 80% of the fatalities. We report a pilot study of 41 patients with nonmetastatic, locoregionally advanced disease (85% of the patients had a nodal status greater than or equal to N2C-N3; 43% had T4 primaries), during which we used a combination of 100 mg of cisplatin/m2 on day 1, 15 mg of bleomycin by intravenous push and 12 mg/m2 by continuous infusion on days 1-5, and 70 mg of epirubicin/m2 on day 1 every 21 days for three cycles before definitive radiation therapy with 70 Gy for 7 weeks. Twenty-seven of 41 patients (66%; 95% confidence interval = 52.5%-80.5%) achieved a clinical complete response, and 40 of 41 (98%) had a major objective response after chemotherapy. Two deaths were treatment related, but side effects were moderate, and the overall treatment sequence was feasible. At the end of radiation therapy, all 39 assessable patients were in complete response, with a median follow-up of 21+ months (greater than 10-greater than 31); 33 (80%) patients had no evidence of disease. We believe that such a complete response rate in a high-volume disease with the use of combined modality treatment indicates a therapeutic gain in UCNT. Researchers performing a multicenter international controlled trial will test this hypothesis and compare local control, disease-free, and overall survival of the therapeutic sequence presented here with radiotherapy alone.
Increased expression of p38 MAPK in human bronchial epithelium after lipopolysaccharide exposure
Authors: E. Roos-Engstrand, A. Wallin, A. Bucht, J. Pourazar, T. Sandström, A. Blomberg
Journal: European Respiratory Journal (2005)

Bacterial endotoxin (lipopolysaccharides (LPS)) is normally present in the wall of Gram-negative bacteria and has potent pro-inflammatory properties. Exposure to LPS has been shown to induce neutrophilic airway inflammation in humans. The aim of this investigation was to study the early inflammatory responses to LPS exposure in human airway mucosa in vivo . In total, 15 healthy nonsmoking volunteers participated. Bronchoscopy was performed on two separate occasions, 3 h after saline inhalation and after inhalation of 50 μg LPS in saline. Endobronchial mucosal biopsy specimens were taken and stained immunohistochemically using a panel of monoclonal antibodies directed against mitogen-activated protein kinases (MAPKs), transcription factors, cytokines, adhesion molecules and inflammatory cells. Expression of p38 MAPK increased as a consequence of LPS exposure, as determined by both total epithelial staining and nuclear location. These two responses were strongly associated. Epithelial expression of interleukin-8 showed a tendency towards a significant increase after LPS compared to saline. Epithelial mast cell numbers were increased after LPS, whereas neutrophil numbers were unchanged. Inhalation of lipopolysaccharide induced activation of the bronchial epithelium, as demonstrated 3 h after exposure by increased expression of p38 mitogen-activated protein kinase and interleukin-8, and may represent early regulatory steps in the subsequent development of a neutrophilic bronchial inflammation.
CD133 Is Not Present on Neurogenic Astrocytes in the Adult Subventricular Zone, but on Embryonic Neural Stem Cells, Ependymal Cells, and Glioblastoma Cells
Authors: Cosima V. Pfenninger, Teona Roschupkina, Falk Hertwig, Denise Kottwitz, Elisabet Englund, Johan Bengzon, Sten Eirik Jacobsen, Ulrike A. Nuber
Journal: Cancer Research (2007)

Abstract Human brain tumor stem cells have been enriched using antibodies against the surface protein CD133. An antibody recognizing CD133 also served to isolate normal neural stem cells from fetal human brain, suggesting a possible lineage relationship between normal neural and brain tumor stem cells. Whether CD133-positive brain tumor stem cells can be derived from CD133-positive neural stem or progenitor cells still requires direct experimental evidence, and an important step toward such investigations is the identification and characterization of normal CD133-presenting cells in neurogenic regions of the embryonic and adult brain. Here, we present evidence that CD133 is a marker for embryonic neural stem cells, an intermediate radial glial/ependymal cell type in the early postnatal stage, and for ependymal cells in the adult brain, but not for neurogenic astrocytes in the adult subventricular zone. Our findings suggest two principal possibilities for the origin of brain tumor stem cells: a derivation from CD133-expressing cells, which are normally not present in the adult brain (embryonic neural stem cells and an early postnatal intermediate radial glial/ependymal cell type), or from CD133-positive ependymal cells in the adult brain, which are, however, generally regarded as postmitotic. Alternatively, brain tumor stem cells could be derived from proliferative but CD133-negative neurogenic astrocytes in the adult brain. In the latter case, brain tumor development would involve the production of CD133. [Cancer Res 2007;67(12):5727–36]
Prospective Study of the Effect of Blood Pressure on Renal Function in Old Age
Authors: Thomas van Bemmel, Karen Woittiez, Gerard J Blauw, Femke van der Sman-de Beer, Friedo W Dekker, Rudi G J Westendorp, Jacobijn Gussekloo
Journal: Journal of the American Society of Nephrology (2006)

High BP is associated with decline of renal function. Whether this is true for very old people largely is unknown. Therefore, this study assessed the effect of BP on creatinine clearance over time in very old participants. A total of 550 inhabitants (34% men) of Leiden, The Netherlands, were enrolled in a population-based study at their 85th birthday and followed until death or age 90. BP was measured twice at baseline and at age 90 yr. Creatinine clearance was estimated annually (Cockcroft-Gault formula). The mean creatinine clearance at baseline was 45.4 ml/min (SD 11.5). Systolic BP was not associated with changes in creatinine clearance during follow-up. Those with diastolic BP (DBP) <70 mmHg had an accelerated decline of creatinine clearance (1.63 ml/min per yr) compared with those with DBP between 70 and 79 mmHg (1.21 ml/min per yr; P = 0.01), 80 to 89 mmHg (1.26 ml/min per yr; P = 0.03), and >89 mmHg (1.38 ml/min per yr; P = 0.32). Participants with a decline in systolic BP during follow-up had an accelerated decline of creatinine clearance compared with those with stable BP (1.54 [SE 0.09] versus 0.98 ml/min per yr [SE 0.09]; P < 0.001). Similar results were found for a decline in DBP (1.54 [SE 0.10] versus 1.06 ml/min per yr [SE 0.08]; P < 0.001). In the oldest individual, high BP is not associated with renal function. In contrast, low DBP is associated with an accelerated decline of renal function. The clinical implications of these findings have to be studied.
A comparison of maximum inspiratory and expiratory flow in health and in lung disease
Authors: J. Jordanoglou, N. B. Pride
Journal: Thorax (1968)

Maximum flow-volume (M.F.-V.) curves for both inspiration and expiration have been obtained in healthy subjects and in patients with bullous emphysema, exacerbation of asthma, and with severe fibrosis of the lungs. The tracheobronchial collapse pattern on the conventional spirogram or the M.F.-V. curve appeared to be related to the severity of airways obstruction more than to the type of airways obstruction. The pattern was observed in exacerbation of asthma as well as in emphysema and occurred when forced expirations were started from low in the vital capacity in normal subjects. The expiratory M.F.-V. slope was normal or steeper than normal in fibrosis and was much lower than normal in asthma and emphysema. In patients with fibrosis maximum expiratory flow (M.E.F.) and maximum inspiratory flow (M.I.F.) at 50% of vital capacity were both reduced and the ratio between them was similar to that in healthy subjects. In both asthma and emphysema there was a low M.E.F.<sub>50%</sub>/M.I.F.<sub>50%</sub> ratio; the only patient with airways obstruction who had a normal M.E.F./M.I.F. ratio was a woman with tracheal stenosis. A theoretical analysis suggests that most forms of airways obstruction would be expected to lead to a greater impairment of M.E.F. than of M.I.F. The M.F.-V. curve did not help in distinguishing a patient with asthma from one with emphysema, but the changes in tracheal obstruction were distinctive.
Exogenous BMPR2 modulates TGF-β signalling in human small airway epithelium and smooth muscle cells
Authors: Feng Feng, Paul N. Reynolds
Journal: European Respiratory Journal (2012)

Introduction  Idiopathic Pulmonary Arterial Hypertension (IPAH) is a fatal disease characterized by reduced BMPR2 and increased TGF-β expression.   Aims and objectives  To investigate the effects of upregulation of BMPR2 on TGF-β signalling in human small airway epithelial cells (hSAEC) and pulmonary artery smooth muscle cells (hPASMC)   Methods  The BMPR2 gene was delivered to both hSAEC and hPASMC using a plasmid construct or Adenovirus vector, then TGF-β signalling events assessed.   Results  In hSAEC, TGF-β upregulated P-38MAPK phosphorylation and vimentin but downregulated pancytokeratin, consistent with epithelial to mesenchymal transition (EMT). In preliminary studies, prior transduction to upregulate BMPR2, ameliorated the TGF-β-induced increase in vimentin. In hPASMC, TGF-β did not affect P-38MAPK, but led to a substantial increase in phosphorylated ERK 42/44 and Smad2, and reduced phosphorylation of Smad1/5/8. These effects were largely prevented by BMPR2 transduction.   Conclusions  To date, these findings suggest that BMPR2 gene delivery reduces TGF-β-induced epithelial to mesenchymal transition and TGF-β signalling in smooth muscle cells.   Supported by : Australian NHMRC.
Human chorionic gonadotropin (hCG) regression normograms for patients with high-risk gestational trophoblastic neoplasia treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) chemotherapy
Authors: C. Lybol, K. Westerdijk, F.C.G.J. Sweep, P.B. Ottevanger, L.F.A.G. Massuger, C.M.G. Thomas
Journal: Annals of Oncology (2012)
Fibrolipomatous hamartoma of the nerve: A clinicopathologic report of 13 cases
Authors: Jose A. Plaza, Dmitry V. Kazakov, Gabriel Casas, Luis Requena, Onofre Sanmartin, Denisa Kacerovska, Michal Michal, Alena Schmoranzova, Saul Suster, Martin Sangueza
Journal: Journal of the American Academy of Dermatology (2014)
Erratum: Increased Risk of Asthma in Patients with Systemic Lupus Erythematosus
Authors: Te-Chun Shen, Chih-Yen Tu, Cheng-Li Lin, Chang-Ching Wei, Yu-Fen Li
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

of asthma could be caused by lupus pulmonary involvement; however, there is insufficient evidence that asthma is a result of lupus interstitial pneumonitis or pleuritis. To the best of our knowledge, a restrictive functional defect was observed in lupus pneumonitis, interstitial pulmonary fibrosis, and pleural effusion, which differed from an obstructive functional defect in asthma (7). Therefore, SLE plays an extremely important role in the development of asthma. With increasing age, other risk factors also contribute to the incidence of asthma, and the relative risk of asthma consequently decreases. Adult-onset asthma is believed to be an underestimated issue, affecting approximately 4–8% of patients older than 65 years (8). A review article by Eagan and coworkers reported that the pooled estimated incidence of adult asthma from general population cohort studies was 59 and 44 per 10,000 person-years in women and men, respectively (9). These findings were close to the incidence found in our non-SLE elderly groups. We believe a small proportion of cases are misclassified as asthma; however, these contributions should be equivalent in the two cohorts. In conclusion, the incidence of asthma may increase in patients with SLE with increasing age, and the data clearly demonstrate that IRR decreases inversely with increasing age. n
Vitamin B deficiency may increase risk of lung cancer
Authors: O. Hashmi
Journal: Thorax (2010)

It has been hypothesised that deficiencies in B vitamin levels may influence gene expression by means of aberrant methylation patterns as vitamin B is essential for DNA synthesis and methylation. This study investigated the role of B vitamins (B2, B6, B9, B12) and methionine status on the development of lung cancer. It was …
Highly Heterogeneous Rates of Evolution in the SKP1 Gene Family in Plants and Animals: Functional and Evolutionary Implications
Authors: Hongzhi Kong, Jim Leebens-Mack, Weimin Ni, Claude W dePamphilis, Hong Ma
Journal: Molecular Biology and Evolution (2004)

Skp1 (S-phase kinase-associated protein 1) is a core component of SCF ubiquitin ligases and mediates protein degradation, thereby regulating eukaryotic fundamental processes such as cell cycle progression, transcriptional regulation, and signal transduction. Among the four components of the SCF complexes, Rbx1 and Cullin form a core catalytic complex, an F-box protein acts as a receptor for target proteins, and Skp1 is an adaptor between one of the variable F-box proteins and Cullin. Whereas protists, fungi, and some vertebrates have a single SKP1 gene, many animal and plant species possess multiple SKP1 homologs. It has been shown that the same Skp1 homolog can interact with two or more F-box proteins, and different Skp1 homologs from the same species sometimes can interact with the same F-box protein. In this paper, we demonstrate that multiple Skp1 homologs from the same species have evolved at highly heterogeneous rates. Parametric bootstrap analyses suggested that the differences in evolutionary rate are so large that true phylogenies were not recoverable from the full data set. Only when the original data set were partitioned into sets of genes with slow, medium, and rapid rates of evolution and analyzed separately, better-resolved relationships were observed. The slowly evolving Skp1 homologs, which are relatively highly conserved in sequence and expressed widely and/or at high levels, usually have very low d(N)/d(S) values, suggesting that they have evolved under functional constraint and serve the most fundamental function(s). On the other hand, the rapidly evolving members are structurally more diverse and usually have limited expression patterns and higher d(N)/d(S) values, suggesting that they may have evolved under relaxed or altered constraint, or even under positive selection. Some rapidly evolving members may have lost their original function(s) and/or acquired new function(s) or become pseudogenes, as suggested by their expression patterns, d(N)/d(S) values, and amino acid changes at key positions. In addition, our analyses revealed several monophyletic groups within the SKP1 gene family, one for each of protists, fungi, animals, and plants, as well as nematodes, arthropods, and angiosperms, suggesting that the extant SKP1 genes within each of these eukaryote groups shared only one common ancestor.
Approval Summary: Sunitinib for the Treatment of Imatinib Refractory or Intolerant Gastrointestinal Stromal Tumors and Advanced Renal Cell Carcinoma
Authors: Vicki L. Goodman, Edwin P. Rock, Ramzi Dagher, Roshni P. Ramchandani, Sophia Abraham, Jogarao V.S. Gobburu, Brian P. Booth, S. Leigh Verbois, David E. Morse, Cheng Yi Liang, Nallaperumal Chidambaram, Janet X. Jiang, Shenghui Tang, Kooros Mahjoob, Robert Justice, Richard Pazdur
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To describe the Food and Drug Administration (FDA) review and approval of sunitinib malate (Sutent). Sunitinib received regular approval for the treatment of gastrointestinal stromal tumor (GIST) after disease progression or intolerance to imatinib mesylate (Gleevec). Additionally, sunitinib received accelerated approval for the treatment of advanced renal cell carcinoma. Experimental Design: For the GIST indication, FDA reviewed data from a randomized, placebo-controlled trial with supportive evidence from a single-arm study. For the advanced renal cell carcinoma indication, FDA reviewed data from two single-arm studies of patients with cytokine-refractory metastatic renal cell carcinoma. Results: In patients with imatinib refractory or intolerant GIST, time-to-tumor progression of sunitinib-treated patients was superior to that of placebo-treated patients. Median time-to-tumor progression of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (P &amp;lt; 0.0001). Partial responses were observed in 6.8% of sunitinib-treated patients. In patients with metastatic renal cell carcinoma, partial responses were observed in 25.5% (95% confidence interval, 17.5, 34.9) and 36.5% (95% confidence interval, 24.7, 49.6) of patients treated with sunitinib. Median response durations were 27.1 and 54 weeks. The most common adverse events attributed to sunitinib included diarrhea, mucositis, skin abnormalities, and altered taste. Reductions in left ventricular ejection fraction and severe hypertension were also more common in sunitinib-treated patients. Conclusions: On January 26, 2006, the FDA approved sunitinib for the treatment of patients with imatinib refractory or intolerant GIST. Accelerated approval was granted for the treatment of advanced renal cell carcinoma.
In Vivo Inhibition of Elevated Myocardial β-Adrenergic Receptor Kinase Activity in Hybrid Transgenic Mice Restores Normal β-Adrenergic Signaling and Function
Authors: Shahab A. Akhter, Andrea D. Eckhart, Howard A. Rockman, Kyle Shotwell, Robert J. Lefkowitz, Walter J. Koch
Journal: Circulation (1999)

Background —The clinical syndrome of heart failure (HF) is characterized by an impaired cardiac β-adrenergic receptor (βAR) system, which is critical in the regulation of myocardial function. Expression of the βAR kinase (βARK1), which phosphorylates and uncouples βARs, is elevated in human HF; this likely contributes to the abnormal βAR responsiveness that occurs with β-agonist administration. We previously showed that transgenic mice with increased myocardial βARK1 expression had impaired cardiac function in vivo and that inhibiting endogenous βARK1 activity in the heart led to enhanced myocardial function. Methods and Results —We created hybrid transgenic mice with cardiac-specific concomitant overexpression of both βARK1 and an inhibitor of βARK1 activity to study the feasibility and functional consequences of the inhibition of elevated βARK1 activity similar to that present in human HF. Transgenic mice with myocardial overexpression of βARK1 (3 to 5-fold) have a blunted in vivo contractile response to isoproterenol when compared with non-transgenic control mice. In the hybrid transgenic mice, although myocardial βARK1 levels remained elevated due to transgene expression, in vitro βARK1 activity returned to control levels and the percentage of βARs in the high-affinity state increased to normal wild-type levels. Furthermore, the in vivo left ventricular contractile response to βAR stimulation was restored to normal in the hybrid double-transgenic mice. Conclusions —Novel hybrid transgenic mice can be created with concomitant cardiac-specific overexpression of 2 independent transgenes with opposing actions. Elevated myocardial βARK1 in transgenic mouse hearts (to levels seen in human HF) can be inhibited in vivo by a peptide that can prevent agonist-stimulated desensitization of cardiac βARs. This may represent a novel strategy to improve myocardial function in the setting of compromised heart function.
Distribution of blood monocytes between a marginating and a circulating pool.
Authors: R van Furth, W Sluiter
Journal: The Journal of Experimental Medicine (1986)

Studies on the blood volume of SPF Swiss mice in the steady state led to reevaluation of the distribution of monocytes in the blood compartment. It was concluded from the results of our calculations that monocytes entering the circulation are distributed over a circulating and a marginating pool. The circulating pool accounts for approximately 40%, and the marginating pool or approximately 60% of the population of peripheral blood monocytes.