tbuckley/cabot-search huggingface dataset:
Acute Molecular Changes in Synovial Fluid Following Human Knee Injury: Association With Early Clinical Outcomes
Authors: Fiona E. Watt, Erin Paterson, Andrew Freidin, Mark Kenny, Andrew Judge, Jeremy Saklatvala, Andy Williams, Tonia L. Vincent
Journal: Arthritis & Rheumatology (2016)

Objective To investigate whether molecules found to be up‐regulated within hours of surgical joint destabilization in the mouse are also elevated in the analogous human setting of acute knee injury, how this molecular response varies between individuals, and whether it is related to patient‐reported outcomes in the 3 months after injury. Methods Seven candidate molecules were analyzed in blood and synovial fluid (SF) from 150 participants with recent structural knee injury at baseline (&lt;8 weeks from injury) and in blood at 14 days and 3 months following baseline. Knee Injury and Osteoarthritis Outcome Score 4 (KOOS 4 ) was obtained at baseline and 3 months. Patient and control samples were compared using Meso Scale Discovery platform assays or enzyme‐linked immunosorbent assay. Results Six of the 7 molecules were significantly elevated in human SF immediately after injury: interleukin‐6 (IL‐6), monocyte chemotactic protein 1, matrix metalloproteinase 3 (MMP‐3), tissue inhibitor of metalloproteinases 1 (TIMP‐1), activin A, and tumor necrosis factor–stimulated gene 6 (TSG‐6). There was low‐to‐moderate correlation with blood measurements. Three of the 6 molecules were significantly associated with baseline KOOS 4 (those with higher SF IL‐6, TIMP‐1, or TSG‐6 had lower KOOS 4 ). These 3 molecules, MMP‐3, and activin A were all significantly associated with greater improvement in KOOS 4 over 3 months, after adjustment for other relevant factors. Of these, IL‐6 alone significantly accounted for the molecular contribution to baseline KOOS 4 and change in KOOS 4 over 3 months. Conclusion Our findings validate relevant human biomarkers of tissue injury identified in a mouse model. Analysis of SF rather than blood more accurately reflects this response. The response is associated with patient‐reported outcomes over this early period, with SF IL‐6 acting as a single representative marker. Longitudinal outcomes will determine if these molecules are biomarkers of subsequent disease risk.
Comparison of three methods for detecting epidermal growth factor receptor mutations in plasma DNA samples of Chinese patients with advanced non-small cell lung cancer.
Authors: W. M. Zhao
Journal: Journal of Clinical Oncology (2010)

e18017 Background: Detecting epidermal growth factor receptor (EGFR) mutations in plasma DNA samples in patients with advanced non-small cell lung cancer is challenging and promising. We compared three methods for detecting plasma EGFR mutations, including direct DNA sequencing, denaturing high-performance liquid chromatography (DHPLC) and Scorpions amplification refractory mutation system (Scorpions ARMS). Methods: Plasma DNA samples from 73 patients with stages IIIB to IV non-small cell lung cancer patients with adenocarcinoma histology were analyzed for EGFR mutations in exons 19 (deletion mutation) and 21 (L858R mutation) by using direct DNA sequencing, DHPLC and Scorpions ARMS . Results: In 73 patients, we detected EGFR mutations in 5 samples (6.85%) by direct DNA sequencing, in 22 samples (30.1%) by DHPLC, and in 28 samples (38.4%) by Scorpions ARMS. we found 13 deletion mutations and 9 L858R mutations by DHPLC, while 15 deletion mutations and 13 L858R mutations by Scorpions ARMS. Among the 73 patients, there was 90.4% concordance between DHPLC and Scorpions ARMS (66/73, κ = 0.71, p < 0.01). Seven patients were detected discordant mutation status by DHPLC and Scorpions ARMS. Six EGFR mutation-positive samples detected by Scorpions ARMS were found mutation-negative by DHPLC, and one EGFR mutation-positive sample detected by DHPLC was found mutation-negative by Scorpions ARMS. In the 73 patients, 46 patients were treated with gefitinib or erlotinib, including 18 patients with mutations and 28 patients without mutations by Scorpions ARMS. The 18 patients with EGFR mutations had a significant longer progression-free survival (PFS) time (median PFS, 21.0 months; 95% confidence interval [CI] 7.5 to 34.5 months) than 28 patients without EGFR mutations (median PFS, 7.0 months; 95% confidence interval [CI] 3.4 to 10.6 months) (p = 0.022). Conclusions: Among the three methods for detecting EGFR mutations in plasma DNA samples in patients with advanced lung adenocarcinoma, direct gene sequencing had the lowest sensitivity, while Scorpion ARMS showed the highest mutation detecting capability. DHPLC is slightly less sensitive than Scorpion ARMS. No significant financial relationships to disclose.
Unexpected Effect of Proton Pump Inhibitors
Authors: Yohannes T. Ghebremariam, Paea LePendu, Jerry C. Lee, Daniel A. Erlanson, Anna Slaviero, Nigam H. Shah, James Leiper, John P. Cooke
Journal: Circulation (2013)

Background— Proton pump inhibitors (PPIs) are gastric acid–suppressing agents widely prescribed for the treatment of gastroesophageal reflux disease. Recently, several studies in patients with acute coronary syndrome have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events. The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed. Methods and Results— Plasma asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely because of its attenuation of the vasoprotective effects of endothelial nitric oxide synthase. We find that PPIs elevate plasma ADMA levels and reduce nitric oxide levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues. PPIs increase ADMA because they bind to and inhibit dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA. Conclusions— We present a plausible biological mechanism to explain the association of PPIs with increased major adverse cardiovascular events in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with the use of the PPIs in the general population.
p53 as a marker of prognosis in African American (AA) women with breast cancer
Authors: K. A. Dookeran, J. Dignam, K. Ferrer, M. Sekosan, W. McCaskill-Stevens, S. Gehlert
Journal: Journal of Clinical Oncology (2009)

e22119 Background: Prior reports suggest that p53 may be of prognostic value in AA women with breast cancer. However, it remains to be determined whether p53 status would add prognostic value beyond the commonly used factors of stage and Intrinsic Subtype Classification (subtype). We evaluated p53 status as a prognostic factor among AA women treated at an urban community hospital. Methods: Cox proportional hazards regression models [results reported as hazard ratios (HR) with 95% confidence intervals (CI)] were used to select and evaluate prognostic factors [including stage, age, tumor grade of differentiation (grade), p53 status, subtype, &amp; ER/PR status] for all-cause mortality in 331 consecutively treated AA women with breast cancer [42 months follow-up] and known subtype [luminal A = ER+, &amp;/or PR+, &amp; HER2-; luminal B = ER+, &amp;/or PR+, &amp; HER2+; HER2+ = ER-, PR-, &amp; HER2+; basal = ER-, PR-, HER2-, cytokeratin (CK) 5/6+ &amp;/or HER1+; &amp; unclassified = negative for all 5 markers] and p53 [Pab1801 antibody] immunohistochemical status. Results: Tumors in 28% of women were p53+ and there were no chemotherapy and radiation treatment differences according to p53 status. However, 59% of p53+ women were ER/PR negative [Odds Ratio (OR), 0.37; 95% CI, 0.22–0.54; p=0.0003] and hence endocrine therapy was significantly less frequent in p53+ women [OR, 0.40; 95% CI, 0.23–0.69; p=0.0008]. p53+ tumors were also significantly more likely to be grade 3 [OR, 4.35; CI, 1.33–14.14; p=0.013]. Baseline prognostic factors were: stage [(II-IV/I) HR, 2.29; 95% CI, 1.86–2.81; p&lt;0.0001]; age [HR, 1.003 per year; 95% CI, 0.99–1.02; p=0.697]; grade [(high/low) HR, 1.70; 95% CI, 1.22–2.37; p=0.0008]; p53 status [(±) HR, 1.76; 95% CI, 1.15–2.72; p=0.012]; subtype [(all other/luminal A) HR, 1.33; 95% CI, 1.14–1.55; p=0.0004]; ER/PR status [(±) HR, 0.47; 95% CI, 0.32–0.69; p=0.0001]. Cox multivariable models indicated that p53 status [HR, 1.59; 95% CI, 1.01–2.51; p=0.044] remained a significant prognostic factor when considered with stage [HR, 2.20; 95% CI, 1.71–2.84; p&lt;0.001] and subtype [HR, 1.24; 95% CI, 1.04–1.49; p=0.016] and the other above-mentioned factors. Conclusions: Study results indicate that p53 status should be included with stage and subtype as markers to assess prognosis in AA women with breast cancer. No significant financial relationships to disclose.
Evidence for distinct vascular and tubular urea transporters in the rat kidney.
Authors: D Promeneur, G Rousselet, L Bankir, P Bailly, J P Cartron, P Ripoche, M M Trinh-Trang-Tan
Journal: Journal of the American Society of Nephrology (1996)

Facilitated urea transport has been demonstrated in several mammalian tissues, including those of the collecting ducts and red blood cells. Two urea transporters have been recently cloned: UT2, expressed in rabbit inner medullary collecting ducts, and HUT11, expressed in human erythrocytes. Because of significant identity (63%) between these two transporters, and because HUT11 is also expressed in the human kidney, they could represent the same transporter with species-related differences in their-sequences. In the study presented here, two different cDNA fragments, corresponding to the rat equivalents (rUT2 and rUT11) of the two previously cloned urea transporters, were isolated by reverse transcription-polymerase chain reaction. These rat probes were used for Northern analysis of RNA extracted from rat tissues. From the following findings, the results show that rUT2 and rUT11 are two distinct urea transporters: (1) The two cDNA fragments isolated in the rat exhibit different sequences; (2) The mRNA for rUT2 is found exclusively in the kidney, with two transcripts (3.2- and 4.4-kilobase (kb)), whereas rUT11 (only one transcript, 4.2 kb) is present in the brain, spleen, kidney, and testis; (3) in the kidney, the inner stripe of the outer medulla expresses rUT11 mRNA and the short transcript of rUT2, whereas the inner medulla expresses rUT11 and the two rUT2 transcripts; (4) In hydronephrotic kidneys that have completely lost their tubular epithelium but have intact vasculature, rUT2 transcripts are no longer expressed, whereas expression of rUT11 is intensified; (5) Experimental chronic alterations in urine concentrating activity induced different changes in the expression of rUT2 and rUT11.
Adjuvant chemotherapy (CT) with doxorubicin and ifosfamide in resected soft tissue sarcoma (STS): Interim analysis of a randomised phase III trial
Authors: P. J. Woll, M. van Glabbeke, P. Hohenberger, A. Le Cesne, A. Gronchi, H. J. Hoekstra, J. A. Radford, F. van Coevorden, J. Blay
Journal: Journal of Clinical Oncology (2007)

10008 Background: The impact of adjuvant CT on survival for resected STS remains uncertain. In a 1997 meta-analysis, doxorubicin-based CT significantly improved local and overall relapse free survival (RFS), but not overall survival. Many of the CT regimens used would now be considered suboptimal. We therefore undertook a multicentre randomised trial of intensive CT in patients with excised high grade STS. Methods: Patients with macroscopically resected, Trojani grade II-III STS at any site, no metastases, performance status (PS) &lt;2 and age = 70 were eligible within 4 weeks of surgery. Patients were randomised to observation or CT with 5 cycles of doxorubicin 75 mg/m 2 , ifosfamide 5 g/m 2 q 21 days and lenograstim. Patients in both arms received radiotherapy (RT) if the resection was marginal or the tumor recurrent. Stratifications were for institution, disease site, tumor size, planned RT and isolated limb perfusion therapy. Results: Between 1995 and 2003, 351 patients were recruited. 9.5% were ineligible and 4.8% did not receive the allocated treatment. Patient characteristics were evenly distributed between the two arms: 47% &gt; 50 years; 54% male; 33% PS 1. The commonest pathological subtypes were leiomyo- 15%, lipo- 13%, MFH 11%, synovial sarcoma 11%. 60% were grade III. 66% were extremity tumors. Of 175 patients allocated CT, 163 started and 127 completed 5 cycles. 38% had dose reductions or delays, mostly for hematologic toxicity or infection. 88% of patients received RT. An interim analysis for futility has been performed, because survival in the observation arm was better than expected: estimated 5-yr RFS was 52% in both arms and OS 69% (observation arm) and 64% (CT arm). The hypotheses that adjuvant CT improves RFS and OS (with hazard ratios = 0.621) can both be rejected. Conclusions: This is the largest study of adjuvant CT with ifosfamide and doxorubicin ever undertaken in STS. It fails to show a survival advantage for adjuvant CT. Improved survival over previous studies might be due to better surgery and increased use of adjuvant RT. Further analysis of this study will allow more detailed assessment of the role of adjuvant CT in resected STS and will contribute to an updated meta-analysis. [Table: see text]
Accuracy Of Adverse Event Reporting Compared To Patient Chart Abstraction On a Phase III NCI-Funded Clinical Trial For Pediatric Acute Myeloid Leukemia: A Report From The Children’s Oncology Group
Authors: Tamara P. Miller, Marko Kavcic, Yimei Li, Todd A. Alonzo, Matt Hall, Yuan-Shung Huang, Robert B. Gerbing, Brian T. Fisher, Selina Luger, David Rubin, Andrea Troxel, Lillian Sung, Alan S. Gamis, Richard Aplenc
Journal: Blood (2013)
Factors associated with bilateral versus single mastectomy in a diverse, population-based sample of breast cancer patients
Authors: S. Hawley, R. Jagsi, A. S. Hamilton, J. Graff, J. J. Griggs, S. J. Katz
Journal: Journal of Clinical Oncology (2009)

6502 Background: Rates of bilateral mastectomy are increasing in the U.S., even among women with cancer in only one breast. The goal of this analysis was to assess correlates of bilateral mastectomy in a large, racially/ethnically diverse sample of breast cancer patients. Methods: All women with ductal carcinoma-in-situ and a 20% random sample of women with invasive breast cancer aged &lt; 79 years who were diagnosed in 2002 and reported to the Detroit and Los Angeles SEER registries were surveyed shortly after receipt of surgical treatment (response rate, 77.4%; n = 1,844). Patient survey data were merged with SEER data. The primary dependent variable, receipt of bilateral mastectomy, was obtained from patient report and validated by SEER. Independent variables included patient demographics, family history of breast cancer, tumor stage, and patient concerns about recurrence and body image. Logistic regression was used to evaluate factors associated with receipt of all mastectomy (including bilateral) vs. lumpectomy, and then to evaluate bilateral vs. single mastectomy. Results: The mean age was 60 years. 70% were white, 18% Black, and 12% Latina. Overall, 5% of women received bilateral mastectomy (13% of those getting mastectomy). The Table shows factors associated with receipt of any mastectomy vs. lumpectomy (model 1) and bilateral vs. single mastectomy (model 2). Advanced stage and concerns about recurrence were associated with increased odds of any mastectomy while body image concerns were associated with lumpectomy (P&lt;0.05) (model 1). Model 2 shows family history (OR: 3.00; 95% CI 1.36–6.61) and concerns about recurrence (OR: 2.76, 95% CI 1.14–6.68) were associated with greater odds of receiving bilateral vs. single mastectomy. Conclusions: Decision making for any mastectomy vs. lumpectomy is quite different from that for bilateral vs. single mastectomy. The latter appears to be driven by genetic predisposition, but there continues to be a strong influence of women's concerns about recurrence. [Table: see text] No significant financial relationships to disclose.
Antibacterial prophylaxis with levofloxacin following myelosuppressive chemotherapy: results of a randomised, double-blind, placebo-controlled trial in 1565 patients
Authors: N. Steven, M. Cullen, L. Billingham, C. Gaunt, M. Hastings
Journal: Journal of Clinical Oncology (2004)

8006 Background: The role of prophylactic antibacterials for patients receiving chemotherapy for solid tumours and lymphoma has remained controversial despite meta-analysis of 749 patients in 9 small trials, many of which had serious methodological weaknesses. Reported here is a placebo-controlled, double-blind, randomised trial, designed to resolve this controversy and inform clinical practice. Methods: Patients with solid tumour or lymphoma about to commence a programme of cyclical chemotherapy with a risk of temporary severe neutropenia (<0.5x109/l) were stratified according to infection risk factors including tumour site, then randomised to receive levofloxacin 500mg od. or matching placebo od. for 7 days to cover the expected period of neutropenia. Patients received the same trial medication for every cycle of chemotherapy (up to 6). Routine GCSF was not permitted at trial entry and subsequent use necessitated discontinuation of trial medication. The primary endpoint was clinically documented febrile episodes, i.e. temperature >38oC attributed to infection. Secondary endpoints included incidence of all probable infections, hospitalisation and severity of infection. Results: The data included patients with different malignancies including breast (35%), lung (22%), testicular cancers (14%), lymphoma (13%) and others (16%). Randomisation resulted in 784 patients allocated placebo and 781 levofloxacin. The febrile episode rate on the first cycle was 8% on placebo versus 4% on levofloxacin (χ2 test, p=0.0002). Two-thirds of patients contributed at least 4 cycles. During chemotherapy, at least one febrile episode occurred in 16% of patients on placebo compared to 11% on levofloxacin (χ2 test, p=0.01). Of the patients on placebo, 42% experienced at least one probable infection compared to 35% receiving prophylaxis (χ2 test, p= 0.005). The rate of hospitalisation differed for patients on the two arms of the trial (placebo 23% versus levofloxacin 17%; χ2 test, p=0.004). Sepsis syndrome was reported for 16 cycles on placebo versus 8 on levofloxacin. There were 8 infection-related deaths, balanced across the two treatment arms. Toxicity attributed to trial medication (principally rash and gastrointestinal symptoms) was reported for <2% of all cycles with a non-significant excess in the levofloxacin arm (χ2 test, p= 0.10). Conclusions: In patients receiving chemotherapy for solid tumours and lymphoma, the use of prophylactic levofloxacin reduces the rate of fever, probable infection and hospitalisation with minimal toxicity. No significant financial relationships to disclose.
Abstract 12879: C/ebp Homologous Protein Deficiency Attenuates Myocardial Ischemia-Reperfusion Injury by Inhibiting Endoplasmic Reticulum Stress-Induced Apoptosis and Inflammation
Authors: Yuji Miyazaki, Koichi Kaikita, Eiji Horio, Megumi Yamamuro, Kenichi Tsujita, Seiji Hokimoto, Hisao Ogawa, Yuichi Oike
Journal: Circulation (2010)

Myocardial ischemia-reperfusion (I/R) injury is currently problematic, but its molecular mechanisms have not been fully clarified. In general, various pathophysiological stimuli trigger endoplasmic reticulum (ER) stress, and excessive response against ER stress is thought to promote apoptosis through activating C/EBP homologous protein (CHOP)-mediated pathway. Therefore, we focused our investigation on the role of CHOP in myocardial I/R injury. Wild-type (WT) and CHOP deficient (CHOP−/−) mice were subjected to 50 min of myocardial ischemia followed by reperfusion. ER stress as assessed by induction of CHOP, phosphorylation of eIF2α and splicing of XBP1 was rapidly and significantly increased at 30 min after reperfusion in WT mice compared with sham-operated mice (p<0.05). The injury size was markedly reduced in CHOP−/− mice at 8 h after reperfusion compared with WT mice (13.9±1.3% versus 44.8±1.7%, p<0.01), accompanied with decreasing number of TUNEL-positive cardiomyocytes (1.5±0.2% versus 10.4±1.9%, p<0...
Inhibition of G Protein βγ Subunit Signaling Abrogates Nephritis in Lupus‐Prone Mice
Authors: Javier Rangel‐Moreno, Jesi Y. To, Teresa Owen, Bruce I. Goldman, Alan V. Smrcka, Jennifer H. Anolik
Journal: Arthritis & Rheumatology (2016)

Objective Despite considerable advances in the understanding of systemic lupus erythematosus (SLE), there is still an urgent need for new and more targeted treatment approaches. We previously demonstrated that small‐molecule blockade of G protein βγ subunit (Gβγ) signaling inhibits acute inflammation through inhibition of chemokine receptor signal transduction. We undertook this study to determine whether inhibition of Gβγ signaling ameliorates disease in a mouse model of SLE. Methods Lupus‐prone (NZB × NZW)F1 female mice were prophylactically or therapeutically treated with the small‐molecule Gβγ inhibitor gallein. Tissue samples were analyzed by flow cytometry and immunohistochemistry. The development and extent of nephritis were assessed by monitoring proteinuria and by immunohistochemical analysis. Serum immunoglobulin levels were measured by enzyme‐linked immunosorbent assay, and total IgG and anti–double‐stranded DNA (anti‐dsDNA) antibody–secreting cells were measured by enzyme‐linked immunospot assay. Results Gallein inhibited accumulation of T cells and germinal center (GC) B cells in the spleen. Both prophylactic and therapeutic treatment reduced GC size, decreased antibody‐secreting cell production in the spleen, and markedly decreased accumulation of autoreactive anti‐dsDNA antibody–secreting cells in kidneys. Gallein also reduced immune complex deposition in kidneys. Finally, gallein treatment dramatically inhibited kidney inflammation, prevented glomerular damage, and decreased proteinuria. Mechanistically, gallein inhibited immune cell migration and signaling in response to chemokines in vitro, which suggests that its mechanisms of action in vivo are inhibition of migration of immune cells to sites of inflammation and inhibition of immune cell maturation. Conclusion Overall, these data demonstrate the potential use of gallein or novel inhibitors of Gβγ signaling in SLE treatment.
Polymorphisms of the tumor necrosis factor-α gene promoter predict for outcome after thalidomide therapy in relapsed and refractory multiple myeloma
Authors: Kai Neben, Joannis Mytilineos, Thomas M. Moehler, Astrid Preiss, Alwin Kraemer, Anthony D. Ho, Gerhard Opelz, Hartmut Goldschmidt
Journal: Blood (2002)