tbuckley/cabot-search huggingface dataset:
Suppression of Retinoic Acid Receptor in Non-Small-Cell Lung Cancer In Vivo: Implications for Lung Cancer Development
Authors: X.-C. Xu, G. Sozzi, J. S. Lee, J. J. Lee, U. Pastorino, S. Pilotti, J. M. Kurie, W. K. Hong, R. Lotan
Journal: JNCI Journal of the National Cancer Institute (1997)

Retinoids, analogues of vitamin A, are required for the normal growth and differentiation of human bronchial epithelium. They are also able to reverse premalignant lesions and prevent second primary tumors in some patients with non-small-cell lung cancer (NSCLC). These effects are thought to result from modulation of cell growth, differentiation, or apoptosis (programmed cell death). When certain retinoid receptors in the cell nucleus (i.e., retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which mediate most retinoid actions, are suppressed, abnormal activity may result that could enhance cancer development.This study was designed to determine whether there are abnormalities in the expression of retinoid receptors in surgical specimens from patients with NSCLC.Transcripts of nuclear retinoid receptors were detected in formalin-fixed, paraffin-embedded specimens by use of digoxigenin-labeled riboprobes specific for RAR alpha, RAR beta, RAR gamma, RXR alpha, RXR beta, and RXR gamma for in situ hybridization to histologic specimens from 79 patients with NSCLC and as control from 17 patients with non-lung cancer. The quality and specificity of the digoxigenin-labeled probes were determined by northern blotting, and the specificity of the binding of antisense riboprobes was verified by use of sense probes as controls.All receptors were expressed in at least 89% of control normal bronchial tissue specimens from 17 patients without a primary lung cancer and in distant normal bronchus specimens from patients with NSCLC. RAR alpha, RXR alpha, and RXR gamma were expressed in more than 95% of the NSCLC specimens. In contrast, RAR beta, RAR gamma, and RXR beta expression was detected in only 42%, 72%, and 76% of NSCLC, respectively.These data suggest that the expression of RAR alpha, RXR alpha, and RXR gamma is not altered in NSCLC; however, expression of RAR beta and possibly also of RAR gamma and RXR beta is suppressed in a large percentage of patients with lung cancer.The loss of expression of one or more of these nuclear retinoid receptors may be associated with lung carcinogenesis.
European survey of fertility and pregnancy in women with Crohn's disease: a case control study by European collaborative group.
Authors: J F Mayberry, I T Weterman
Journal: Gut (1986)

Two hundred and seventy five patients with Crohn9s disease from five countries were interviewed. Each patient was matched with a control of the same age. Of the 275 women with Crohn9s disease 224 had been married at some time compared with 208 controls. The mean age at marriage was 23 years. Diagnosis of Crohn9s disease was made five years later and the survey was conducted on average 16 years after marriage. Cases and controls had a similar obstetric study before diagnosis. After diagnosis there was a significant reduction in the number of children born to patients (0.4) compared with controls (0.7). Crohn9s disease did not increase the rate of miscarriage or Caesarean section but prematurity was more common in patients (16%) than controls (7%). The site of disease at diagnosis did not affect these findings. Medical advice against pregnancy may be partly responsible for this reduction in fertility, but patients practised contraception less than controls and a significantly greater proportion of these (42%) failed to become pregnant compared with controls (28%). Crohn9s disease results in subfertility.
TLE6 mutation causes the earliest known human embryonic lethality
Authors: Anas M. Alazami, Salma M. Awad, Serdar Coskun, Saad Al-Hassan, Hadia Hijazi, Firdous M. Abdulwahab, Coralie Poizat, Fowzan S. Alkuraya
Journal: Genome biology (2015)

Embryonic lethality is a recognized phenotypic expression of individual gene mutations in model organisms. However, identifying embryonic lethal genes in humans is challenging, especially when the phenotype is manifested at the preimplantation stage. In an ongoing effort to exploit the highly consanguineous nature of the Saudi population to catalog recessively acting embryonic lethal genes in humans, we have identified two families with a female-limited infertility phenotype. Using autozygosity mapping and whole exome sequencing, we map this phenotype to a single mutation in TLE6, a maternal effect gene that encodes a member of the subcortical maternal complex in mammalian oocytes. Consistent with the published phenotype of mouse Tle6 mutants, embryos from female patients who are homozygous for the TLE6 mutation fail to undergo early cleavage, with resulting sterility. The human mutation abrogates TLE6 phosphorylation, a step that is reported to be critical for the PKA-mediated progression of oocyte meiosis II. Furthermore, the TLE6 mutation impairs its binding to components of the subcortical maternal complex. In this first report of a human defect in a member of the subcortical maternal subcritical maternal complex, we show that the TLE6 mutation is gender-specific and leads to the earliest known human embryonic lethality phenotype.
Parathyroid hormone inhibits B cell proliferation
Authors: J M Alexiewicz, M Klinger, T O Pitts, Z Gaciong, M Linker-Israeli, S G Massry
Journal: Journal of the American Society of Nephrology (1990)

B cell proliferation is impaired in patients with chronic renal failure, but the mechanisms underlying this defect are not known. Lymphocytes have receptors for parathyroid hormone, and it is possible that the state of secondary hyperparathyroidism of renal failure is responsible for the B cell defect. Our studies were designed to (a) examine T cell-independent B cell proliferation [3H)thymidine incorporation) induced by Staphylococcus aureus Cowan 1 after 5 days of culture, (b) evaluate the effect of parathyroid hormone on S. aureus Cowan I-induced B cell proliferation, and (c) investigate the mechanisms through which parathyroid hormone may exert its effect on B cell proliferation. Lymphocytes were obtained from 37 normal subjects and 21 dialysis patients. S. aureus Cowan I induced significant stimulation (P less than 0.01) of the proliferation of B cells from both groups, but the effect was smaller on B cells from dialysis patients (10.0 x 10(3) +/- 1.4 x 10(3) cpm) than on those from normal subjects (21.8 x 10(3) +/- 2.0 x 10(3) cpm). Both the intact molecule of parathyroid hormone (1-84 PTH) and its amino-terminal fragment (1-34 PTH) caused significant inhibition of proliferation of B cells from normal subjects in a dose-dependent manner, with the effect being significantly greater (P less than 0.01) with an equimolar concentration of 1-84 PTH than that of 1-34 PTH. Inactivation of 1-84 PTH by oxidation abolished most of its inhibitory effect on B cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
Predictors for Failure of Pneumocystis carinii Pneumonia Prophylaxis
Authors: Alfred J. Saah
Journal: JAMA (1995)

Objective.  —To identify clinical and epidemiological factors associated with failure of Pneumocystis carinii pneumonia (PCP) prophylaxis in those receiving primary and secondary prophylaxis.  Design.  —Longitudinal cohort study of participants infected with human immunodeficiency virus type 1 in the Multicenter AIDS Cohort Study who used PCP prophylaxis regimens after their T-helper lymphocyte counts had decreased to less than 0.200×10 9 /L (200/μL).  Main Outcome Measure.  —Occurrence or recurrence of PCP.  Results.  —A total of 476 participants reported taking one or more of the following regimens: trimethoprim-sulfamethoxazole (TMP-SMX), dapsone, and/or aerosolized pentamidine—367 as primary prophylaxis and 109 as secondary prophylaxis after a previous episode of PCP. A total of 92 (20%) developed PCP despite prophylaxis. The mean failure rates per person-year of follow-up were 16.0% for those receiving primary prophylaxis and 12.1% for those receiving secondary prophylaxis ( P =.19). Median times to death after initiation of primary or secondary prophylaxis were 2.0 and 1.2 years, respectively. The main predictor for failure of PCP prophylaxis was profound T-helper lymphocytopenia; 86% of failures occurred after T-helper cell counts decreased to less than 0.075×10 9 /L and 76% occurred after counts decreased to less than 0.050×10 9 /L. In multivariate time-dependent analysis, when compared with counts between 0.100×10 9 /L and 0.200×100 9 /L, the risk ratio for failure with counts less than 0.050×10 9 /L was 2.90 ( P  P =.01). Use of TMP-SMX as the prophylaxis regimen was protective but did not eliminate failure (ie, a time-dependent risk ratio of 0.55; P =.03).  Conclusions.  —These findings strongly support identifying improved methods of PCP prophylaxis once T-helper cell counts decrease to less than 0.075×10 9 /L or 0.100×10 9 /L. Given this severe degree of immunosuppression, an inherently more effective regimen against P carinii is required.  ( JAMA . 1995;273:1197-1202)
AEE788, a Dual Tyrosine Kinase Receptor Inhibitor, Induces Endothelial Cell Apoptosis in Human Cutaneous Squamous Cell Carcinoma Xenografts in Nude Mice
Authors: Young Wook Park, Maher N. Younes, Samar A. Jasser, Orhan G. Yigitbasi, Ge Zhou, Corazon D. Bucana, Benjamin N. Bekele, Jeffrey N. Myers
Journal: Clinical Cancer Research (2005)

Abstract Purpose: We investigated whether concomitant blockade of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways by AEE788, a dual inhibitor of EGFR and VEGFR tyrosine kinases, would inhibit the growth of cutaneous squamous cell carcinoma (SCC) cells and human cutaneous cancer xenografts in nude mice. Experimental Design: We examined the effects of AEE788 on the phosphorylation of EGFR and VEGFR-2 in cutaneous SCC cells expressing EGFR and VEGFR-2 and cutaneous SCC cell growth and apoptosis. We assessed the in vivo antitumor effects of AEE788 in a xenograft model in nude mice. AEE788 (50 mg/kg) was given orally thrice weekly to mice that had been s.c. injected with Colo16 tumor cells. Mechanisms of in vivo AEE788 activity were determined by immunohistochemical analysis. Results: Treatment of cutaneous SCC cells with AEE788 led to dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation, growth inhibition, and induction of apoptosis. In mice treated with AEE788, tumor growth was inhibited by 54% at 21 days after the start of treatment compared with control mice (P &amp;lt; 0.01). Immunohistochemical analysis revealed that AEE788 inhibited phosphorylation of EGFR and VEGFR and induced apoptosis of tumor cells and tumor-associated endothelial cells. Conclusions: In addition to inhibiting cutaneous cancer cell growth by blocking EGFR and VEGFR signaling pathways in vitro, AEE788 inhibited in vivo tumor growth by inducing tumor and endothelial cell apoptosis.
Three pertinent issues in the modeling of brain activity: Nonlinearities, time scales, and neural underpinnings
Authors: A. Daffertshofer, T. D. Frank, C. E. Peper, P. J. Beek
Journal: Behavioral and Brain Sciences (2000)

A critical discussion is provided of three central assumptions underlying Nunez's approach to modeling cortical activity. A plea is made for neurophysiologically realistic models involving nonlinearities, multiple time scales, and stochasticity.
Myocardial damage and valve replacements
Authors: H. M. Singh, E. H. Horton
Journal: Thorax (1971)

Forty patients who came to necropsy over a period of five years due to myocardial damage sustained during cardiac valve replacements were studied. The clinical presentation of myocardial damage was assessed in relation to the preoperative cardiac status. The cause and nature of myocardial damage were assessed at necropsy. Evidence of clinical, electrocardiographic and aortographic coronary atheroma was correlated with distribution at necropsy, and the value of selective coronary angiography in perfusing the coronary arteries during cardiopulmonary bypass is stressed. The causes of myocardial damage could be classified as (<i>a</i>) thrombo-embolic, (<i>b</i>) iatrogenic damage to the coronary arteries, and (<i>c</i>) poor or absent coronary perfusion during cardiopulmonary bypass. A case is made for the importance of coronary perfusion during cardiopulmonary bypass.
Abstract 4390: Metronomic maintenance chemotherapy of orally active pemetrexed for effective treatment of lung cancer
Authors: Foyez Mahmud, Seho Kweon, Hyo Won Chang, Hae Yoon Nam, Mi Ra Kim, Jung Je Park, Sang Yoon Kim, Youngro Byun
Journal: Cancer Research (2015)

Abstract At present, most of the anticancer drugs are given parenterally, showing drug concentration above the maximum tolerable concentration (MTC) followed by rapid elimination from the plasma that causes enhanced side effects and lower efficacy. In contrast, low dose oral maintenance therapy may increase therapeutic efficacy by increasing the exposure time to cancer cells and also reduce the side effects by maintaining the drug concentration below MTC level. Pemetrexed is a folate antagonist approved for maintenance chemotherapy in lung cancer. However, a major limitation of Pemetrexed is the poor oral bioavailability which imposes IV administration. In this context, we have developed a physical complex of Pemetrexed with lysine conjugated deoxycholic acid (DCK) in water (mole ratio 1:2) for the purpose of oral delivery. The DSC thermogram of Pemetrexed/DCK complex showed the complex formation due to disappearance of exothermic and endothermic peaks from Pemetrexed. The pharmacokinetic studies of Pemetrexed/DCK were done in SD rats and analyzed by HPLC method. In antitumor study, low dose continuous oral therapy from 2.5 mg/kg to 20 mg/kg showed substantial tumor inhibition in SCC7 tumor bearing C3H mice. We also evaluated maintenance chemotherapy as oral Pemetrexed/DCK administration in A549 tumor bearing nude mice. We found that 5 mg/kg dose of oral Pemetrexed successfully inhibited tumor progression and also showed additional antitumor effects when given with Cisplatin as maintenance chemotherapy. In the context of oral anticancer drugs, we need to consider the toxicities in GI tracts (GIT). For this purpose, apoptosis in GI tracts and morphology of different organs were assessed by TUNEL and H&amp;E staining. One month toxicity studies have been conducted in nude mice and we found that 5 mg/kg oral dose did not produce any abnormalities in hematological and serological parameters in mice having intact morphology of GI tracts. Our studies offer safe and effective oral maintenance chemotherapy of pemetrexed for cancer patients at home. Citation Format: Foyez Mahmud, Seho Kweon, Hyo Won Chang, Hae Yoon Nam, Mi Ra Kim, Jung Je Park, Sang Yoon Kim, Youngro Byun. Metronomic maintenance chemotherapy of orally active pemetrexed for effective treatment of lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4390. doi:10.1158/1538-7445.AM2015-4390
Human Papillomavirus DNA versus Papanicolaou Screening Tests for Cervical Cancer
Authors: Marie-Hélène Mayrand, Eliane Duarte-Franco, Isabel Rodrigues, Stephen D. Walter, James Hanley, Alex Ferenczy, Sam Ratnam, François Coutlée, Eduardo L. Franco
Journal: New England Journal of Medicine (2007)

To determine whether testing for DNA of oncogenic human papillomaviruses (HPV) is superior to the Papanicolaou (Pap) test for cervical-cancer screening, we conducted a randomized trial comparing the two methods.
Treatment Outcomes in the STAR Study: A Subanalysis of Solifenacin 5 mg and Tolterodine ER 4 mg
Authors: Christopher R. Chapple, Aino Fianu-Jonsson, Mark Indig, Vik Khullar, José Rosa, Roberto M. Scarpa, Arun Mistry, D. Mark Wright, John Bolodeoku
Journal: European Urology (2007)
Endogenous Myelin Basic Protein Inactivates the High Avidity T Cell Repertoire
Authors: Oleg S. Targoni, Paul V. Lehmann
Journal: The Journal of Experimental Medicine (1998)

To study the contribution of endogenous myelin basic protein (MBP) to the positive and/or negative selection of the MBP-specific T cell repertoire, we studied the T cell response to MBP in MBP-deficient shiverer and MBP-expressing congenic C3H mice. Immunization with MBP induced a vigorous T cell response in shiverer mice directed against a single I-Ak– restricted immunodominant determinant, the core of which is peptide MBP:79-87 (DENPVVHFF). Injection of this peptide induced a high avidity T cell repertoire in shiverer mice that primarily consisted of clones capable of recognizing the native MBP protein in addition to the peptide itself. These data show that endogenous MBP is not required for the positive selection of an MBP-specific T cell repertoire. C3H mice, in contrast, were selectively unresponsive to the MBP protein and injection of MBP:79-87 peptide induced a low avidity repertoire that could be stimulated only by the peptide, not by the protein. Therefore, endogenous MBP induced profound inactivation of high avidity clones specific for the immunodominant determinant making that determinant appear cryptic.
Spearman’s rank correlation coefficient
Authors: Philip Sedgwick
Journal: BMJ (2014)

Researchers examined the association between trends in antidepressant prescribing and suicide rates between 1991 and 2000 in Australia.1 A retrospective analysis of national databases was undertaken. Participants were aged 15 years or more. The primary outcomes were trends in suicide rates and antidepressant prescribing, according to sex and 10 year age groups. The trend in suicide within each age group was measured by the difference between the suicide rates per 100 000 people in two five year periods (1986-90 and 1996-2000). Trends in antidepressant prescribing were assessed by the change in defined daily dose per 1000 days, as indicated by the difference between 1991 and 2000. A positive trend in suicide rates or antidepressant prescribing within an age group represented an increase from 1991 to 2000.

The researchers reported that although overall national rates of suicide did not fall significantly, the incidence decreased in older men and women and increased in younger adults. Rates of antibiotic prescribing increased across all age groups in both men and women. The association between trends in suicide rates and antidepressant prescribing were measured by Spearman’s rank correlation coefficient. There was an inverse correlation between trends in antidepressant prescribing and suicide; with the largest declines in suicide in the age groups with the greatest increase in exposure to antidepressants. The association was significant in women ( rs =−0.74; P<0.05) but not in men ( r s=−0.62; P<0.10).

It was concluded that an increase in antidepressant prescribing may be a proxy marker for improved overall management of depression. If so, increased prescribing of selective serotonin reuptake inhibitors in general practice may have a quantifiable benefit on the mental health of the population.

Which of the following statements, if any, are true?
Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage
Authors: Craig S Anderson, Emma L Heeley, Yining Huang, Ji-Guang Wang, Christian Stapf, Candice Delcourt, Richard I Lindley, Thompson G Robinson, Pablo M Lavados, Bruce Neal, Jun Hata, Hisatomi Arima, Mark W Parsons, Yuechun Li, Jinchao Wang, Stephane Roland Heritier, Qiang Li, Mark Woodward, R John Simes, Stephen M Davis, John P Chalmers
Journal: New England Journal of Medicine (2013)

Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known.We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician's choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups.Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively.In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.).
Smoking in Crohn's disease: effect on localisation and clinical course.
Authors: E Lindberg, G Jarnerot, B Huitfeldt
Journal: Gut (1992)

The effects of smoking on the localisation and clinical course of Crohn9s disease is evaluated in 231 patients. Heavy smokers (greater than 10 cigarettes/day) had an increased risk of operation at least once--odds ratios for heavy smokers compared with never smokers after five and 10 years were 1.14 and 1.24 respectively (p = 0.03 and p = 0.017). The risk of further operations was even higher and after 10 years the odds ratio was 1.79 (p = 0.015). The accumulated number of fistulae and/or abscesses was higher for smokers than for never smokers (p = 0.046). Patients with a high life time tobacco exposure (greater than 150 cigarette years) and heavy smokers (greater than 10 cigarettes/day) had small bowel disease more often than patients with lower life time exposure (less than or equal to 150 cigarette years) and patients smoking less than or equal to 10 cigarettes/day (p = 0.002 and p = 0.045 respectively). The course of Crohn9s disease analysed in different ways was unfavourable for smokers, especially heavy smokers. Patients with Crohn9s disease should be dissuaded from smoking.