tbuckley/cabot-search huggingface dataset:
The tumor suppressive role of miRNA-370 by targeting FoxM1 in acute myeloid leukemia
Authors: Xiaolu Zhang, Jiping Zeng, Minran Zhou, Bingnan Li, Yuanyuan Zhang, Tao Huang, Lixiang Wang, Jihui Jia, Chunyan Chen
Journal: Molecular Cancer (2012)

Abstract Background Recent evidence has accumulated that MicroRNA (miRNA) dysregulation occurs in the majority of human malignancies including acute myeloid leukemia (AML) and may contribute to onco-/leukemo-genesis. Methods The expression levels of miR-370 and FoxM1 were assessed in 48 newly diagnosed AML patients, 40 AML patients in 1 st complete remission (CR) and 21 healthy controls. Quantitative real-time PCR, western blots, colony formation assay, and β-Galactosidase ( SA - β-Gal) staining were used to characterize the changes induced by overexpression or inhibition of miR-370 or FoxM1. Results We found that the down-regulation of miR-370 expression was a frequent event in both leukemia cell lines and primary leukemic cells from patients with de novo AML. Lower levels of miR-370 expression were found in 37 of 48 leukemic samples from AML patients compared to those in bone marrow cells derived from healthy adult individuals. Ectopic expression of miR-370 in HL60 and K562 cells led to cell growth arrest and senescence. In contrast, depletion of miR-370 expression using RNA interference enhanced the proliferation of those leukemic cells. Mechanistically, miR-370 targets the transcription factor FoxM1, a well established oncogenic factor promoting cell cycle progression. Moreover, when HL60 and K562 cells were treated with 5-aza-2 ′ -deoxycytidine, a DNA methylation inhibitor, miR-370 expression was up-regulated, which indicates epigenetic silencing of miR-370 in leukemic cells. Conclusions Taken together, miR-370 may function as a tumor suppressor by targeting FoxM1, and the epigenetic silence of miR-370 thus leads to derepression of FoxM1 expression and consequently contributes to AML development and progression.
MiR-451 inhibits cell growth and invasion by targeting MIF and is associated with survival in nasopharyngeal carcinoma
Authors: Na Liu, Ning Jiang, Rui Guo, Wei Jiang, Qing-Mei He, Ya-Fei Xu, Ying-Qin Li, Ling-Long Tang, Yan-Ping Mao, Ying Sun, Jun Ma
Journal: Molecular Cancer (2013)

Abstract Background MiRNAs play important roles in diverse biological processes including tumorigenesis. However, little is known about the function and mechanism of miR-451 in nasopharyngeal carcinoma (NPC). Methods Quantitative RT-PCR was used to quantify miR-451 expression in NPC cell lines and clinical tissues. Kaplan-Meier curves were used to estimate the association between miR-451 expression and survival. The MTT, colony formation, Transwell migration and invasion assays, and a xenograft model were performed. A miR-451 target was confirmed using luciferase reporter assays, quantitative RT-PCR, and Western blotting. Results MiR-451 was significantly downregulated in NPC cell lines and clinical tissues ( P &lt; 0.01). Patients with low expression of miR-451 had poorer overall survival (HR, 1.98; 95% CI, 1.16-3.34; P = 0.01) and disease-free survival (HR, 1.68; 95% CI, 1.07-2.62; P = 0.02) than patients with high expression. MiR-451 was an independent prognostic factor in NPC in multivariate Cox regression analysis. Ectopic expression of miR-451 suppressed cell viability, colony formation, and cell migration and invasion in vitro, and inhibited xenograft tumor growth in vivo. MIF was verified as a direct target of miR-451, and MIF regulated NPC cell growth and invasion. Conclusions The newly identified miR-451/ MIF pathway provides insight into NPC initiation and progression, and may represent a novel therapeutic target.
Sorafenib for the Treatment of Advanced Renal Cell Carcinoma
Authors: Robert C. Kane, Ann T. Farrell, Haleh Saber, Shenghui Tang, Gene Williams, Josephine M. Jee, Chengyi Liang, Brian Booth, Nallaperumal Chidambaram, David Morse, Rajeshwari Sridhara, Patricia Garvey, Robert Justice, Richard Pazdur
Journal: Clinical Cancer Research (2006)

Abstract Purpose: This report describes the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar, BAY43-9006), a new small-molecule, oral, multi-kinase inhibitor for the treatment of patients with advanced renal cell carcinoma (RCC). Experimental Design: After meeting with sponsors during development studies of sorafenib, the FDA reviewed the phase 3 protocol under the Special Protocol Assessment mechanism. Following new drug application submission, FDA independently analyzed the results of two studies in advanced RCC: a large, randomized, double-blinded, phase 3 international trial of single-agent sorafenib and a supportive phase 2 study. Results: In the phase 3 trial, 902 patients with advanced progressive RCC after one prior systemic therapy were randomized to 400 mg sorafenib twice daily plus best supportive care or to a matching placebo plus best supportive care. Primary study end points included overall survival and progression-free survival (PFS). A PFS analysis, pre-specified and conducted after a total of 342 events, showed statistically significant superiority for the sorafenib group (median = 167 days) compared with that for the controls (median = 84 days, log-rank P &amp;lt; 0.000001); the sorafenib/placebo hazard ratio was 0.44 (95% confidence interval, 0.35-0.55). Results were similar regardless of patient risk score, performance status, age, or prior therapy. The (partial) response rate to sorafenib was 2.1%. Overall survival results are preliminary. The principal toxicities in the sorafenib patients included reversible skin rashes in 40% and hand-foot skin reaction in 30%; diarrhea was reported in 43%, treatment-emergent hypertension was reported in 17%, and sensory neuropathic changes were reported in 13%. Grade 4 adverse events were uncommon. Grade 3 adverse events were hand-foot skin reaction (6%), fatigue (5%), and hypertension (3%). Laboratory findings included asymptomatic hypophosphatemia in 45% of sorafenib patients versus 11% in the placebo arm and elevation of serum lipase in 41% of sorafenib patients versus 30% in the placebo arm. Grade 4 pancreatitis was reported in two sorafenib patients, although both patients subsequently resumed sorafenib, with one at full dose. Conclusions: Sorafenib received FDA regular approval on December 20, 2005 for the treatment of advanced RCC based on the persuasive magnitude of improvement in PFS with acceptable safety. The recommended dose is 400 mg (two 200-mg tablets) twice daily taken either 1 h before or 2 h after meals. Adverse events were accommodated by temporary dose interruptions or reductions.
Calpain Activation and Secretion Promote Glomerular Injury in Experimental Glomerulonephritis
Authors: Julie Peltier, Agnès Bellocq, Joëlle Perez, Sophie Doublier, Yi-Chun Xu Dubois, Jean-Philippe Haymann, Giovanni Camussi, Laurent Baud
Journal: Journal of the American Society of Nephrology (2006)

Glomerular injury and albuminuria in acute glomerulonephritis are related to the severity of inflammatory process. Calpain, a calcium-activated cysteine protease, has been shown to participate in the development of the inflammatory process. Therefore, for determination of the role of calpain in the pathophysiology of acute glomerulonephritis, transgenic mice that constitutively express high levels of calpastatin, a calpain-specific inhibitor protein, were generated. Wild-type mice that were subjected to anti-glomerular basement membrane nephritis exhibited elevated levels of calpain activity in kidney cortex at the heterologous phase of the disease. This was associated with the appearance in urine of calpain activity, which originated potentially from inflammatory cells, abnormal transglomerular passage of plasma proteins, and tubular secretion. In comparison with nephritic wild-type mice, nephritic calpastatin-transgenic mice exhibited limited activation of calpain in kidney cortex and limited secretion of calpain activity in urine. This was associated with less severe glomerular injury (including capillary thrombi and neutrophil activity) and proteinuria. There was a reduction in NF-kappaB activation, suggesting that calpain may participate in inflammatory lesions through NF-kappaB activation. There also was a reduction in nephrin disappearance from the surface of podocytes, indicating that calpain activity would enhance proteinuria by affecting nephrin expression. Exposure of cultured podocytes to calpain decreased nephrin expression, and, conversely, exposure of these cells to calpastatin prevented TNF-alpha from decreasing nephrin expression, demonstrating a role for the secreted form of calpain. Thus, both activation and secretion of calpains participate in the development of immune glomerular injury.
Effects of diaphragm activation control on sniff nasal-inspiratory pressure and maximum relaxation rate of inspiratory muscles in healthy subjects
Authors: Fernando Augusto Lavezzo Dias, Ana Cristina Maciel Garcia, Kadja Franciely Gomes Benicio, Ingrid Guerra Azevedo, Vanessa Resqueti, Andrea Aliverti, Guilherme Augusto F. Fregonezi
Journal: European Respiratory Journal (2013)

To study the influence of diaphragmatic activation control ( diaphC ) on sniff nasal-inspiratory pressure (SNIP) and maximum relaxation rate of inspiratory muscles (MRRins) in healthy subjects.Twenty subjects (9 m), age:23±2.3 years, BMI:23.8±3 kg/m2;FEV1/FVC:0.86±0.05) performed 5 sniffs test in two occasions: without instruction on diaphC and with instruction on diaphC in this order.Before the first maneuver without diaphC a brief explanation was gave to the subjects about the sniff test. Sniff test with diaphC subject were instructed to perform a strong diaphragm recruitment.The best maximum SNIP and MRRins were studied in three conditions.The criteria of total sniff duration less than 500ms, peak pressure maximum of 50ms and waveform exhibit a smooth down-stroke were used to analyze appropriate sniff.The MRRins was calculated as the peak rate of pressure decay (dP/dtmax) and were normalized by dividing the maximum rate of change of pressure by peak pressure and expressed as % fall in pressure/10ms.SNIP and MRRins were significant different without and with diaphC .Without diaphC 40% of the sample not comprise the criteria of appropriate sniff.

![Figure][1] 



In conclusion, diaphC significantly influence SNIP but not MRRins.Sniff tests without diaphC reach lowest values of pressure and a tendency of high values of MRRins, presumably due to inspiratory rib cage muscle recruitment.

 [1]: pending:yes
<i>MYO1E</i>Mutations and Childhood Familial Focal Segmental Glomerulosclerosis
Authors: Caterina Mele, Paraskevas Iatropoulos, Roberta Donadelli, Andrea Calabria, Ramona Maranta, Paola Cassis, Simona Buelli, Susanna Tomasoni, Rossella Piras, Mira Krendel, Serena Bettoni, Marina Morigi, Massimo Delledonne, Carmine Pecoraro, Isabella Abbate, Maria Rosaria Capobianchi, Friedhelm Hildebrandt, Edgar Otto, Franz Schaefer, Fabio Macciardi, Fatih Ozaltin, Sevinc Emre, Tulin Ibsirlioglu, Ariela Benigni, Giuseppe Remuzzi, Marina Noris
Journal: New England Journal of Medicine (2011)

Focal segmental glomerulosclerosis is a kidney disease that is manifested as the nephrotic syndrome. It is often resistant to glucocorticoid therapy and progresses to end-stage renal disease in 50 to 70% of patients. Genetic studies have shown that familial focal segmental glomerulosclerosis is a disease of the podocytes, which are major components of the glomerular filtration barrier. However, the molecular cause in over half the cases of primary focal segmental glomerulosclerosis is unknown, and effective treatments have been elusive.
MECHANISMS OF IMMUNOLOGIC INJURY OF RAT PERITONEAL MAST CELLS
Authors: Elmer L. Becker, K. Frank Austen
Journal: The Journal of Experimental Medicine (1966)

The ability of a number of p-nitrophenylethyl, alkyl phenylalkyl, chloroalkyl, and aminoalkyl phosphonates to inhibit the homocytotropic antibody-mediated release of histamine from rat peritoneal mast cells has been tested. The effectiveness of these same phosphonates against the activated first component of rat complement (C'1a) has also been investigated. The rat mast cell esterase activated by the reaction of antigen and homocytotropic antibody resembles chymotrypsin in its reactivity with the phenylalkyl and chloroalkyl phosphonate, but is unlike this protease in its greater responsiveness to the 5-aminopentyl phosphonate relative to the pentyl phosphonate. The antigen-homocytotropic antibody-activated mast cell esterase and chymotrypsin, thus, appear to be similar, but different enzymes; i.e., they are parazymes (see reference 4, p. 501). There are distinct differences in the pattern of inhibition given by the phenylalkyl and aminoalkyl and alkyl phosphonates of the homocytotropic antibody-mediated histamine release from rat peritoneal mast cells and from guinea pig lung slices. On the basis of these differences it is concluded that the esterases activated by the combination of antigen and homocytotropic antibody on the mast cells of the two species are not the same. The arithmetic dose response curve found for the action of the phosphonates on the antigen-induced histamine release from rat peritoneal mast cells contrasted sharply with the logarithmic relationship found when these same inhibitors acted on the guinea pig lung system. This suggests that in addition to the antigen-antibody-activated esterases being unlike, the detailed mode of histamine release from the mast cells of the guinea pig lung differs from that of the mast cells of the rat peritoneum. Distinct and large differences were found in the pattern of inhibition of histamine release from rat peritoneal mast cells and of rat C'1a given by the phenylalkyl, and chloroalkyl and alkyl phosphonates implying that esterase activated by the combination of antigen with the sensitized rat peritoneal mast cells is not C'1a. Thus, the results with the peritoneal mast cells lead to the same conclusion as the previous work with guinea pig lung slices; i.e., the antigen-antibody-activated esterase involved in the homocytotropic antibody-mediated release of histamine is not part of the complement system.
Cross sectional study of primary care groups in London: association of measures of socioeconomic and health status with hospital admission rates
Authors: A. Majeed
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objectives:</b> To calculate socioeconomic and health status measures for the primary care groups in London and to examine the association between these measures and hospital admission rates. <b>Design:</b> Cross sectional study. <b>Setting:</b> 66 primary care groups in London, total list size 8.0 million people. <b>Main outcome measures:</b> Elective and emergency standardised hospital admission ratios; standardised admission rates for diabetes and asthma. <b>Results:</b> Standardised hospital admission ratios varied from 74 to 116 for total admissions and from 50 to 124 for emergency admissions. Directly standardised admission rates for asthma varied from 152 to 801 per 100 000 (mean 364) and for diabetes from 235 to 1034 per 100 000 (mean 538). There were large differences in the mortality, socioeconomic, and general practice characteristics of the primary care groups. Hospital admission rates were significantly correlated with many of the measures of chronic illness and deprivation. The strongest correlations were with disability living allowance (<i>R</i>=0.64 for total admissions and <i>R</i>=0.62 for emergency admissions, P&lt;0.0001). Practice characteristics were less strongly associated with hospital admission rates. <b>Conclusions:</b> It is feasible to produce a range of socioeconomic, health status, and practice measures for primary care groups for use in needs assessment and in planning and monitoring health services. These measures show that primary care groups have highly variable patient and practice characteristics and that hospital admission rates are associated with chronic illness and deprivation. These variations will need to be taken into account when assessing performance.
Practical Dermatopathology, 2nd edn. Ronald P. Rapini. Edinburgh: Elsevier Saunders, 2012; 450 pp. ISBN: 978-0323-06658-7; 978-1-4557-3800-7 (E-book). Price: £118.
Authors: J.C. Cardoso
Journal: British Journal of Dermatology (2013)
Induced Termination of Pregnancy Before and After Roe v Wade
Authors: Yank D. Coble
Journal: JAMA (1992)

The mortality and morbidity of women who terminated their pregnancy before the 1973 Supreme Court decision in Roe v Wade are compared with post— Roe v Wade mortality and morbidity. Mortality data before 1973 are from the National Center for Health Statistics; data from 1973 through 1985 are from the Centers for Disease Control and The Alan Guttmacher Institute. Trends in serious abortion-related complications between 1970 and 1990 are based on data from the Joint Program for the Study of Abortion and from the National Abortion Federation. Deaths from illegally induced abortion declined between 1940 and 1972 in part because of the introduction of antibiotics to manage sepsis and the widespread use of effective contraceptives. Deaths from legal abortion declined fivefold between 1973 and 1985 (from 3.3 deaths to 0.4 death per 100 000 procedures), reflecting increased physician education and skills, improvements in medical technology, and, notably, the earlier termination of pregnancy. The risk of death from legal abortion is higher among minority women and women over the age of 35 years, and increases with gestational age. Legal-abortion mortality between 1979 and 1985 was 0.6 death per 100 000 procedures, more than 10 times lower than the 9.1 maternal deaths per 100 000 live births between 1979 and 1986. Serious complications from legal abortion are rare. Most women who have a single abortion with vacuum aspiration experience few if any subsequent problems getting pregnant or having healthy children. Less is known about the effects of multiple abortions on future fecundity. Adverse emotional reactions to abortion are rare; most women experience relief and reduced depression and distress.  ( JAMA . 1992;268:3231-3239)
Factors that influence the surgical effects of astigmatic keratotomy after cataract surgery
Authors: Tomoyuki Inoue, Naoyuki Maeda, Kaoru Sasaki, Hitoshi Watanabe, Yoshitsugu Inoue, Koji Nishida, Yumiko Inoue, Shuji Yamamoto, Yoshikazu Shimomura, Yasuo Tano
Journal: Ophthalmology (2001)
Autoantibodies to the Thyrotropin Receptor
Authors: BERNARD REES SMITH, SANDRA MELISSA McLACHLAN, JADWIGA FURMANIAK
Journal: Endocrine Reviews (1988)

This review considers recent developments in our understanding of the properties of TRAb, particularly measurement of the antibodies and their sites of action and synthesis. Two new assay methods have allowed considerable improvements in the sensitivity, specificity, precision, and ease of measuring TRAb. In particular: 1) receptor assays based on inhibition of receptor-purified labeled TSH binding to detergent-solubilized TSH receptors and 2) bioassays based on stimulation of cAMP release from monolayer cultures of isolated thyroid cells. Detailed studies with the two assays indicate that TSH receptor antibodies nearly always act as TSH agonists in patients with a history of Graves' hyperthyroidism. Studies in areas of dietary iodine sufficiency suggest that measurement of the antibodies at various stages in the course of treating Graves' disease can be of value in predicting the outcome of therapy. However, in areas of iodine deficiency, difficulties in the ability of patients' thyroid tissue to recover from the effects of antithyroid drugs may prevent the receptor antibodies from causing a relapse of thyrotoxicosis. Consequently, the predictive value of receptor antibody measurements would be expected to be lower in these geographical areas. Although patients with a history of Graves' hyperthyroidism nearly always have TRAb which act as TSH agonists, about 20% of patients with frank hypothyroidism due to autoimmune destruction of the thyroid have TRAb which act as TSH antagonists (blocking antibodies). There is some evidence that these blocking antibodies can cause hypothyroidism particularly in the neonate. With regard to the site of synthesis of TRAb, there is now direct evidence that they are synthesized by thyroid lymphocytes, particularly the lymphocytes in close proximity to thyroid follicular cells. This is consistent with the well established effects of antithyroid treatment (drugs, radioiodine, or surgery) on TRAb levels in addition to their effects on thyroid hormone synthesis. Recent studies using affinity labeling with 125I-labeled TSH have enabled elucidation of the structure of the TSH receptor. TSH receptors in human, porcine, and guinea pig thyroid tissue have a two-chain structure in which the TSH binding site is formed on the outside surface of the cell membrane by a water-soluble A subunit (Mr approximately 50 K). The A subunit is linked by a disulfide bridge and weak noncovalent bonds to the amphiphilic B subunit (Mr approximately 30 K). This subunit, which penetrates the lipid bilayer, probably forms the site for interaction of the receptor with the regulatory subunits of adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
Memantine Protects Rats Treated with Intrathecal Methotrexate from Developing Spatial Memory Deficits
Authors: Peter D. Cole, Veena Vijayanathan, Nafeeza F. Ali, Mark E. Wagshul, Eric J. Tanenbaum, Jeremy Price, Vidhi Dalal, Maria E. Gulinello
Journal: Clinical Cancer Research (2013)

To test whether memantine can prevent methotrexate-induced cognitive deficits in a preclinical model.After noting that methotrexate exposure induces prolonged elevations of the glutamate analog homocysteic acid (HCA) within cerebrospinal fluid, we tested whether intrathecal injection of HCA would produce memory deficits similar to those observed after intrathecal methotrexate. We then tested whether memantine, an antagonist of the N-methyl-d-aspartate (NMDA) subclass of glutamate receptors, could protect animals treated with clinically relevant doses of intrathecal methotrexate against developing memory deficits. Finally, we asked whether memantine affected this pathway beyond inhibiting the NMDA receptor by altering expression of the NMDA receptor or affecting concentrations of HCA or glutamate within the central nervous system.Four intrathecal doses of methotrexate induced deficits in spatial memory, persisting at least one month following the final injection. Intrathecal HCA was sufficient to reproduce this deficit. Concurrent administration of memantine during the period of methotrexate exposure was protective, decreasing the incidence of methotrexate-induced spatial memory deficits from 56% to 20% (P < 0.05). Memantine neither altered expression of NMDA receptors within the hippocampus nor blunted the methotrexate-induced increases in glutamate or HCA.Excitotoxic glutamate analogs including HCA contribute to cognitive deficits observed after intrathecal methotrexate. Memantine, an NMDA receptor antagonist, reduces the incidence of cognitive deficits in rats treated with intrathecal methotrexate, and may therefore benefit patients with cancer receiving similar treatment.
Association of a MicroRNA/TP53 Feedback Circuitry With Pathogenesis and Outcome of B-Cell Chronic Lymphocytic Leukemia
Authors: Muller Fabbri
Journal: JAMA (2011)

Chromosomal abnormalities (namely 13q, 17p, and 11q deletions) have prognostic implications and are recurrent in chronic lymphocytic leukemia (CLL), suggesting that they are involved in a common pathogenetic pathway; however, the molecular mechanism through which chromosomal abnormalities affect the pathogenesis and outcome of CLL is unknown.