tbuckley/cabot-search huggingface dataset:
Diverse effects of PAI-1 proteins on lung and prostate cancer cell invasion
Authors: Adriana Rozy, Marta Kedzior, Joanna Chorostowska-Wynimko, Paulina Jagus, Adam Szpechcinski, Ewa Skrzypczak-Jankun, Jerzy Jankun
Journal: European Respiratory Journal (2011)

Acquisition of ability to uncontrolled migration is one of the fundamental properties of cancer cells, enabling them to infiltrate tissues and metastasize. PAI-1 is the major physiological inhibitor of urokinase (uPA), which plays a key role in migration and invasion of tumor cells. The aim of present study was to analyze the impact of increasing concentrations of PAI-1 mutated forms: VLHL PAI-1 with very long half-life time, Vn neg PAI-1 - devoid of affinity towards vitronectin and wPAI -1 on lung (A549, H1299) and prostate (LNCaP, DU145) cancer cells invasive activity. Selected cell lines are characterized by different (normal and high) urokinase production.  No effect of PAI-1 proteins on invasiveness of lung cancer cells was observed, while dose-dependent significant inhibition was demonstrated in both prostate cancer lines (DU145 and LNCaP) cultured with VLHL PAI-1 (respectively p  PAI-1 inhibitory effect on prostate cancer invasive activity is associated with anti-proteinase activity. Lung cancer cells invasiveness regulation seems not to be PAI-1-urokinase regulated.
<i>ESR1</i> Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients
Authors: David Chu, Costanza Paoletti, Christina Gersch, Dustin A. VanDenBerg, Daniel J. Zabransky, Rory L. Cochran, Hong Yuen Wong, Patricia Valda Toro, Justin Cidado, Sarah Croessmann, Bracha Erlanger, Karen Cravero, Kelly Kyker-Snowman, Berry Button, Heather A. Parsons, W. Brian Dalton, Riaz Gillani, Arielle Medford, Kimberly Aung, Nahomi Tokudome, Arul M. Chinnaiyan, Anne Schott, Dan Robinson, Karen S. Jacks, Josh Lauring, Paula J. Hurley, Daniel F. Hayes, James M. Rae, Ben Ho Park
Journal: Clinical Cancer Research (2015)

Mutations in the estrogen receptor (ER)α gene, ESR1, have been identified in breast cancer metastases after progression on endocrine therapies. Because of limitations of metastatic biopsies, the reported frequency of ESR1 mutations may be underestimated. Here, we show a high frequency of ESR1 mutations using circulating plasma tumor DNA (ptDNA) from patients with metastatic breast cancer.We retrospectively obtained plasma samples from eight patients with known ESR1 mutations and three patients with wild-type ESR1 identified by next-generation sequencing (NGS) of biopsied metastatic tissues. Three common ESR1 mutations were queried for using droplet digital PCR (ddPCR). In a prospective cohort, metastatic tissue and plasma were collected contemporaneously from eight ER-positive and four ER-negative patients. Tissue biopsies were sequenced by NGS, and ptDNA ESR1 mutations were analyzed by ddPCR.In the retrospective cohort, all corresponding mutations were detected in ptDNA, with two patients harboring additional ESR1 mutations not present in their metastatic tissues. In the prospective cohort, three ER-positive patients did not have adequate tissue for NGS, and no ESR1 mutations were identified in tissue biopsies from the other nine patients. In contrast, ddPCR detected seven ptDNA ESR1 mutations in 6 of 12 patients (50%).We show that ESR1 mutations can occur at a high frequency and suggest that blood can be used to identify additional mutations not found by sequencing of a single metastatic lesion.
Effects of statutes requiring psychiatrists to report suspected sexual abuse of children
Authors: F S Berlin, H M Malin, S Dean
Journal: American Journal of Psychiatry (1991)

Reporting of child sexual abuse is mandatory in all 50 states. Conceptual distinctions between privileged communications and mandatory reporting are reviewed, and the impact of recent changes in Maryland's reporting laws is examined.Beginning in 1964 Maryland law required reporting if abuse was suspected when a physician examined a child. In 1988 reporting of disclosures by adult patients about child sexual abuse that occurred while they were in treatment was mandated. In 1989 all patient disclosures, even about such abuse that occurred before treatment, became reportable. During the period of statutory changes, the Johns Hopkins Sexual Disorders Clinic had kept track of adult patients who referred themselves for treatment and adult patients' disclosures of child sexual abuse. This allowed analysis of the impact produced by changes in the reporting requirements.1) Mandatory reporting of disclosures about prior child sexual abuse deterred undetected adult abusers from entering treatment. The rate of self-referrals when such reporting became mandatory in 1989 dropped from approximately seven per year (73 over a 10-year period) to zero. This may have caused some unidentified children to remain at risk. 2) Mandatory reporting deterred patients' disclosures about child sexual abuse that occurred during treatment. In 1988 the disclosure rate during treatment dropped from approximately 21 per year to zero. This deprived clinicians of information important for early intervention. 3) Mandatory reporting failed to increase the number of abused children identified. The number identified secondary to such disclosures was zero.Optimal protection of children, as well as treatment for adult patients, may be better accomplished by legislation that supports options other than reporting.
A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of <i>KIT</i>
Authors: R. D. Carvajal, P. B. Chapman, J. D. Wolchok, L. Cane, J. B. Teitcher, J. Lutzky, A. C. Pavlick, B. C. Bastian, C. R. Antonescu, G. K. Schwartz
Journal: Journal of Clinical Oncology (2009)

9001 Background: Three prior phase II studies of Imatinib mesylate (IM) in 62 pts with advanced melanoma reported only 1 response in a pt with acral melanoma. A proportion of melanomas arising from acral, mucosal, and chronic sun damaged (CSD) sites are characterized by KIT mutations (mut) or amplifications (amp) and we hypothesized that this subset of tumors would be sensitive to IM. We thus designed this phase II study of IM restricted to pts with melanoma harboring such alterations in KIT. Methods: Pts with unresectable melanoma arising from acral, mucosal, and CSD sites whose tumor harbored a 4q12 amp by FISH or mut in KIT and who had measureable disease by RECIST were eligible. Pts received IM 400 mg BID continually. Response was assessed every cycle (6 wks). A Simon 2-stage design was employed where initially 16 pts would be treated; if ≥ 2 responses were observed, a total of 25 pts would be enrolled. If ≥5 responses were seen in 25 pts, the study was to be considered positive. Results: Of 81 pt tumors screened, 17 (21%) had a KITmut or amp: 5/22 (23%) acral, 12/45 (27%) mucosal, 0/13 (0%) CSD, 0/1 (0%) unknown primary. 12 (15%) had a mut only; 4 (5%) had an amplification only; 1 (2%) had both. Thus far, 7 have been treated, with 5 currently evaluable for response. Median age: 64 yrs (range, 61–86); 2 male/5 female; median KPS: 90 (range, 80- 90); median # of prior therapies: 1 (range, 0–4). 3 pts (43%) achieved a PR (18 wks - exon 13 mut; 21 wks, ongoing - exon 11 mut; 18 wks, ongoing - exon 11 mut &amp; amp); 2 pts (28%) achieved SD (12 wks - exon 11 mut; 11 wks - amp). 3 pts required a dose reduction to 400 mg QD for rash, GI toxicity and fatigue. 1 pt required a second dose reduction to 300 mg QD for visual changes. Conclusions: In this pt population, 21% of tumors are characterized by mut or amp of KIT. The 3 responses observed have allowed expansion to the second stage of enrollment which is currently on-going. While IM has limited activity in a non-selected melanoma pt population, a substantial proportion of melanomas harboring KIT mut or amp appear to respond. It may be possible to identify appropriate pts prospectively for treatment with IM. (Supported by R01FD003445–01, ASCO YIA, N01CM62206, and the Live4Life Foundation.) No significant financial relationships to disclose.
Effectiveness and complications of endobronchial coil treatment for lung volume reduction (LVRC) in patients with severe heterogeneous emphysema and bilateral incomplete fissures
Authors: Konstantina Kontogianni, Vasiliki Gerovasili, Daniela Gompelmann, Maren Schuhmann, Philine Kaukel, Claus Peter Heussel, Felix J.F. Herth, Ralf Eberhardt
Journal: European Respiratory Journal (2014)

In this retrospective analysis 42 patients ([male]/[female]:21/21, age: 64±8years) were included. A total of 10 coils were unilaterally implanted in a single lobe. 7 patients received additional treatment of a contralateral lobe. At 90 days follow-up changes in pulmonary function tests (PFT), 6-Minute-Walk-Test (6MWT) and modified Medical Research Council (mMRC) dyspnea scale, as well as possible complications were recorded.   Results : Forced expiratory volume in the 1 st  second (0.70±0.20L vs 0.75±0.23L, p:0.009), vital capacity (2.0±0.70L vs 2.30±0.77L, p  Complication rate was 57% (n=28) in a total of 49 procedures. No mortality has been observed. Light, self-limited hemorrhage occurred in 10 patients (20%) and lung infection that required oral antibiotics in 6 patients (12%). Significant complications included: hemorrhage in 3 patients (6%), which in 1 case required lobectomy, lung infection treated with intravenous antibiotics in 6 patients (12%) and pneumothorax requiring chest–tube draining in 3 patients (6%), which in 2 cases required further surgical treatment due to lung perforation by coils. From the 3 patients that required surgical complication management, 2 were patients that received coil treatment for the second time.   Conclusions : Endoscopic LVRC improved PFT, 6MWT and mMRC up to 90 days post intervention, however a significant complication rate has been noted in our institute which needs further elucidation.
Stage I testicular seminoma: results of adjuvant irradiation and surveillance.
Authors: P Warde, M K Gospodarowicz, T Panzarella, C N Catton, J F Sturgeon, M Moore, P Goodman, M A Jewett
Journal: Journal of Clinical Oncology (1995)

To assess the results of treatment and patterns of relapse in a contemporary group of patients with stage I testicular seminoma managed by adjuvant radiation therapy (RT) and surveillance.Between January 1981 and December 1991, 364 patients with stage I seminoma were treated at Princess Margaret Hospital. Of these, 194 were treated with adjuvant RT (92% received a dose of 25 Gy in 20 fractions for 4 weeks) and 172 were managed by surveillance. Two patients were included in this series twice--both had postorchiectomy RT for stage I disease, developed a contralateral seminoma, and were placed on surveillance and analyzed for outcome of both primary tumors. The median follow-up period for patients treated with adjuvant RT was 8.1 years (range, 0.2 to 12), and for patients managed by surveillance, it was 4.2 years (range, 0.6 to 10.1).The overall 5-year actuarial survival rate for all patients was 97%, and the cause-specific survival rate was 99.7%. Only one patient died of seminoma. Of 194 patients treated with RT, 11 have relapsed, with a 5-year relapse-free rate of 94.5%. Prognostic factors for relapse included histology, tunica invasion, spermatic cord involvement, and epididymal involvement. Twenty-seven patients developed disease progression on surveillance, which resulted in a 5-year progression-free rate of 81.9%. The only factor identified to predict progression on surveillance was age at diagnosis: patients aged < or = 34 years had a 26% risk of progression at 5 years, in contrast to a 10% risk of progression in those greater than 34 years of age.The outcome of patients with stage I testicular seminoma is excellent, with only one of 364 patients (0.27%) dying of disease. In our experience, both a policy of adjuvant RT and of surveillance resulted in a high probability of cure. Our surveillance experience showed that four of five patients with stage I seminoma are cured with orchiectomy alone. The benefit of adjuvant RT was reflected in a decreased relapse rate. We have identified a number of prognostic factors for relapse in patients managed with both approaches, but further study of prognostic factors is required, particularly to identify patients at high risk of disease progression on surveillance.
The Use of Glyburide Compared With Other Sulfonylureas and the Risk of Cancer in Patients With Type 2 Diabetes
Authors: Marco Tuccori, Jennifer W. Wu, Hui Yin, Agnieszka Majdan, Laurent Azoulay
Journal: Diabetes Care (2015)

OBJECTIVE To determine whether the use of glyburide is associated with an increased risk of cancer compared with the use of other second-generation sulfonylureas among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The U.K. Clinical Practice Research Datalink was used to conduct a cohort study among 52,600 patients newly prescribed glyburide or other second-generation sulfonylureas between 1 January 1988 and 31 July 2013. A time-dependent Cox proportional hazards model was used to estimate adjusted hazard ratios (HRs) and 95% CIs of any cancer associated with the use of glyburide compared with the use of second-generation sulfonylureas. Secondary analyses were conducted to determine whether the association varied with cumulative duration of use and cumulative dose (expressed as defined daily dose [DDD]). RESULTS During 280,288 person-years of follow-up, 4,105 patients were given a new diagnosis of cancer (incidence rate 14.6 per 1,000 person-years). Overall, when compared with the use of other second-generation sulfonylureas, the use of glyburide was associated with a nonsignificant increased risk of any cancer (HR 1.09 [95% CI 0.98–1.22]). In secondary analyses, duration- and dose-response relationships were observed, with longer cumulative durations and cumulative doses associated with an increased risk of any cancer (&amp;gt;36 months: HR 1.21 [95% CI: 1.03–1.42]; &amp;gt;1,096 DDDs: HR 1.27 [95% CI 1.06–1.51]). CONCLUSIONS In this population-based cohort study, longer cumulative durations and higher cumulative doses of glyburide were associated with an increased risk of cancer.
Abstract 5383: The Circadian Clock within the Cardiomyocyte is a Novel Mechanism Regulating Myocardial Triglyceride Metabolism
Authors: Ju-Yun Tsai, Vijayalakshmi Nannegari, William C Heird, Martin E Young
Journal: Circulation (2008)

Virtually every mammalian cell, including the cardiomyocyte, has an intrinsic molecular circadian clock. The cardiomyocyte circadian clock has recently been shown to directly mediate diurnal variations in myocardial gene expression, metabolism, and contractile function. This includes modulation of the heart’s acute transcriptional response to increased circulating fatty acids, in a time-of-day-dependent manner. We therefore hypothesized that disruption of the cardiomyocyte circadian clock would impair metabolic adaptation of the heart to high fat feeding. Wild type (WT) and cardiomyocyte-specific circadian clock mutant (CCM) mice were fed either a control or high fat diet (10% and 45% calories from fat, respectively) for 16 weeks, after which myocardial adaptation was assessed at transcriptional, metabolic, and functional levels. Ex vivo mouse heart perfusions in the working mode revealed that high fat feeding induced alterations in myocardial metabolism ( e.g. reduced carbohydrate oxidation; p&lt;0.01) and contractile function ( e.g. depressed cardiac power; p&lt;0.01) in WT, but not CCM, hearts. Furthermore, the ability to decrease reliance on endogenous substrate utilization during an acute increase in fatty acid availability ex vivo was abolished in hearts from CCM mice fed the high fat diet (p&lt;0.05), suggesting potential alterations in triglyceride metabolism. Consistent with the latter, microarray analysis revealed that the cardiomyocyte circadian clock regulates expression of several genes involved in triglyceride turnover. For example, diurnal variations in expression of diacylglycerol acyltransferase 2, which promotes lipogenesis, and rates of myocardial triglyceride synthesis both peak in the middle of the active phase (2- and 3- fold, trough-to-peak, respectively; p&lt;0.05), which are abolished in CCM hearts. These data provide direct evidence that the cardiomyocyte circadian clock regulates myocardial triglyceride metabolism at multiple levels. We postulate that disruption of this intramyocellular mechanism may contribute to altered myocardial metabolism and contractile dysfunction observed during cardiac hypertrophy, diabetes mellitus, and/or shift work.
Only in non-obese patients with COPD MEF50 is strongly associated with dynamic hyperinflation
Authors: Quirine Van Steenwijk, Jop Keuchenius, Christof Majoor, Peter Sterk, Reindert Van Steenwijk
Journal: European Respiratory Journal (2014)

Rationale:   Patients with COPD or Cystic fibrosis (CF) develop obstructive airway disease, which leads to decreased exercise tolerance often due to dynamic hyperinflation (DHI). Measurement of DHI is difficult and requires an incremental exercise test. We hypothesized that MEF50, the expiratory flow after expiration of 50% of the forced vital capacity (FVC), can predict DHI in patients with airway obstruction.   Methods:   During 3 years (2010-2012) all patients with COPD (n=64) or CF (n=11) who had performed an incremental exercise test and spirometry were retrospectively analysed. In the first 50 COPD patients spirometric and incremental exercise test measurements (change in inspiratory capacity at baseline and during exercise (deltaIC)) were evaluated, the other 14 and the 11 CF-patients were used as validation set. Correlations were analysed through linear regression using SPSS.   Results:   50 patients with COPD (aged 57.7 years, 52% male, FEV1 mean 59.9%pred, mean MEF50 32.1%pred) had a mean deltaIC of 350 ml (range -590-1400) with a moderate linear correlation (R 2  0.29 (p 2  of 0.45 (p 2  for BMI >26.0 was non-significant (R 2  0.18, p>0.05). All non-obese patients (BMI  These findings were confirmed in the validation set of COPD patients (age 54 years, mean BMI 26.1) and the 11 CF-patients (aged 27.6 years, BMI 21.7).   Conclusion:   MEF50
Asthma, COPD and overlap syndrome: a longitudinal study in young European adults
Authors: Roberto de Marco, Alessandro Marcon, Andrea Rossi, Josep M. Antó, Isa Cerveri, Thorarinn Gislason, Joachim Heinrich, Christer Janson, Deborah Jarvis, Nino Kuenzli, Bénédicte Leynaert, Nicole Probst-Hensch, Cecilie Svanes, Matthias Wjst, Peter Burney
Journal: European Respiratory Journal (2015)

We compared risk factors and clinical characteristics, 9-year lung function change and hospitalisation risk across subjects with the asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), asthma or COPD alone, or none of these diseases.Participants in the European Community Respiratory Health Survey in 1991-1993 (aged 20-44 years) and 1999-2001 were included. Chronic airflow obstruction was defined as pre-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity<lower limit of normal on both occasions. Based on their history of respiratory symptoms, spirometry and risk factors, subjects were classified as having asthma alone (n=941), COPD alone (n=166), ACOS (n=218) and none of these (n=5659).Subjects with ACOS shared risk factors and clinical characteristics with subjects with asthma alone, but they had an earlier age of asthma onset. FEV1 change in the ACOS group (-25.9 mL·year(-1)) was similar to that in the asthma group (-25.3 mL·year(-1)), and lower (p<0.001) than in the COPD group (-37.3 mL·year(-1)). ACOS was associated with the highest hospitalisation rate.Among young adults aged 20-44 years, ACOS seems to represent a form of severe asthma, characterised by more frequent hospitalisations, and to be the result of early-onset asthma that has progressed to fixed airflow obstruction.
Inhibition of estrogen receptor action by a naturally occurring variant in human breast tumors.
Authors: Fuqua Sa, Fitzgerald Sd, Allred Dc, Elledge Rm, Nawaz Z, McDonnell Dp, O'Malley Bw, Greene Gl, McGuire Wl
Journal: Cancer Research (1992)

It is fairly well accepted that the presence of estrogen receptor (ER) and progesterone receptor (PgR) identifies breast cancer patients with a lower risk of relapse and better overall survival. But patients with discordant receptors, the ER+/PgR- phenotype, are often intermediate in clinical response. We focused upon this group of patients and have identified a truncated ER which is abundant in some ER+/PgR- breast tumors and which inhibits the binding of wild-type ER to its cognate response element. This variant interferes in a dominant negative manner with wild-type ER function and may represent a mechanism for modulation of estrogen responsiveness.
Time to get our acts together
Authors: Clare L Reid, David K Menon
Journal: BMJ (2007)

The Mental Capacity Act 2005 will be implemented during 2007, joining the Human Tissue Act 2004 and the European Union Clinical Trials Directive 2004 in contributing to new legislation that affects clinical research. Input from researchers and academics at the consultation stage has ensured that the resulting legislation will not prohibit vital research in incapacitated patients, as had been …
Insulin-like growth factor receptor 1 (IGF1R) protein expression, mRNA expression and gene copy number in operable non-small cell lung cancer (NSCLC)
Authors: R. Dziadziuszko, D. T. Merrick, S. E. Witta, A. D. Mendoza, B. Szostakiewicz, W. Rzyman, J. Jassem, P. A. Bunn, M. Varella-Garcia, F. R. Hirsch
Journal: Journal of Clinical Oncology (2009)

7524 Background: IGF1R is a promising target for NSCLC therapy. We have evaluated IGF1R protein expression, mRNA expression and gene copy number in primary tumors from surgically treated NSCLC patients (pts) as a reference for correlative biomarker studies in trials using IGF1R inhibitors. Methods: The study included 189 consecutive NSCLC pts who underwent curative pulmonary resection. There were 24% females, 54% squamous cell carcinomas (SCC), 29% adenocarcinomas (AC), 3% large cell carcinomas, 14% other histologies; p stage I: 41%, pII: 22%, pIII: 32% and pIV: 4%. IGF1R expression was evaluated in tissue microarrays by immunohistochemistry (IHC) with Ventana CONFIRM (N=179) and Novus (#NB600–559) anti-IGF1R Ab scored by two observers (H score 0–400). IGF1R gene copy number was assessed by FISH using customized probes (N=181). IGF1R gene expression was evaluated using qRT-PCR from 114 corresponding fresh-frozen samples. Results: Patterns of IHC staining were different for the Ventana and the Novus Ab (inverse correlation, r=-0.16, p=0.04, N=177). IGF1R protein expression detected by Ventana Ab (&gt; median score) was more frequent in SCC (76%) than AC and other histologies (14%, p&lt;0.001) and in pts with higher stage (p=0.03) but was not associated with survival (p=0.46). IGF1R H score by Ventana Ab, but not by Novus Ab, correlated with mRNA expression (r=0.37, p&lt;0.001). IGF1R mRNA expression tended to be higher in SCC than in other histologies (p=0.089), but did not associate with other clinical features or survival (p=0.73). According to criteria previously established for EGFR, IGF1R gene copy number by FISH showed 5 tumors with gene amplification (2.8%), 43 tumors - high polysomy (23.8%), 87 tumors - low polysomy (48.1%), and 46 tumors - trisomy/disomy (25.4%). Pts with gene amplification/high polysomy had 3-yr survival of 60% (95% CI 47% - 74%) vs. 48% (38% - 59%) for low polysomy and 35% (21% - 49%) for trisomy/disomy pts (p=0.016). Prognostic value of IGF1R gene copy number was confirmed in the multivariate analysis. Conclusions: IGF1R protein expression is higher in SCC. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number associates with better prognosis in operable NSCLC. [Table: see text]