tbuckley/cabot-search huggingface dataset:
Functional Significance of Cytochrome <i>P</i>450 1B1 in Endometrial Carcinogenesis
Authors: Sharanjot Saini, Hiroshi Hirata, Shahana Majid, Rajvir Dahiya
Journal: Cancer Research (2009)

Cytochrome P450 1B1 (CYP1B1) catalyzes estrogen hydroxylation and activation of potential carcinogens. Here we explored the role of CYP1B1 in endometrial carcinogenesis. Immunohistochemical staining of endometrial carcinomas showed that CYP1B1 is up-regulated in endometrial cancers. To understand the functional significance of CYP1B1 up-regulation in endometrial cancers with regard to tumorigenesis, we used small interfering RNA-mediated approach to knockdown CYP1B1 in endometrial carcinoma cell line followed by functional assays. Further, to understand the molecular basis of the role of CYP1B1 in endometrial carcinomas, we profiled the expression of key pathway-specific genes and identified several components of cell cycle, apoptosis, and cell adhesion pathways that are potentially regulated by CYP1B1. CYP1B1 depletion in endometrial carcinoma cells leads to decreased cellular proliferation and induces G(0)-G(1) cell cycle arrest. Significantly, CYP1B1 knockdown leads to down-regulated expression of cyclin E1, S-phase kinase-associated protein 2 (SKP2), minichromosome maintenance complex component 4 (MCM4), and RAD51 and up-regulation of p27(Kip1). Also, we identified cyclin E-binding protein (CEBP1) as a novel CYP1B1 target. Attenuation of CYP1B1 expression in endometrial carcinoma cells induces apoptosis and increases expression of IFN-beta (IFNbeta), granzyme A (GRZA), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Importantly, CYP1B1 depletion decreased the invasive potential of the endometrial cancer cells and expression of melanoma cell adhesion molecule (MCAM). In conclusion, our data suggest that CYP1B1 up-regulation plays a crucial role in endometrial carcinogenesis by targeting multiple pathways. We speculate that CYP1B1 inhibition in endometrial carcinomas could be a useful therapeutic approach as it regulates several potential anticancer targets like cyclin E1, Skp2, and TRAIL.
Polymorphisms in the CD14 Gene Associated with Pulmonary Function in Farmers
Authors: Tricia D. LeVan, Susanna Von Essen, Debra J. Romberger, G. Patrick Lambert, Fernando D. Martinez, Monica M. Vasquez, James A. Merchant
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale and Objectives: Farmers experience airway obstruction, which may be attributable in part to endotoxin inhalation. CD14 is a receptor for endotoxin. Materials and Methods: Based on our findings of increased circulating CD14 associated with the CD14/−159 T allele, we hypothesized that carriers of this allele would have decreased lung function among endotoxin-exposed individuals. CD14/−159TT farmers (n = 19) had significantly lower lung function as measured by FEV1 (p = 0.028) and mean forced expiratory flow during the middle half of the FVC (FEF25–75) (p = 0.05) compared with farmers with the C allele (n = 78). Also, farmers with the CD14/−1619GG genotype (n =11) were associated with lower lung function (FEV1, p = 0.008; FEF25–75, p = 0.009) compared with farmers with the A allele (n = 86). Results: No association between CD14/−550 and lung function was observed (FEV1, p = 0.32; FEF25–75, p = 0.11). Increased prevalence of wheezing was reported in farmers homozygous for CD14/−159T (p = 0.013) or CD14/−1619G (p = 0.019) compared with farmers with the CC or AA genotype, respectively. No association was found between TLR4/Asp299Gly and lung function or wheeze. Conclusion: We conclude that the CD14/−159 or CD14/−1619 loci may play a role in modulating lung function and wheeze among agricultural workers.
A Homozygous Mutation in <i>MSH6</i> Causes Turcot Syndrome
Authors: Madhuri R. Hegde, Belinda Chong, Maria E. Blazo, Lip Hon E. Chin, Patricia A. Ward, Murali M. Chintagumpala, John Y. Kim, Sharon E. Plon, C. Sue Richards
Journal: Clinical Cancer Research (2005)

Abstract Heterozygous mutations in one of the DNA mismatch repair genes cause hereditary nonpolyposis colorectal cancer (MIM114500). Turcot syndrome (MIM276300) has been described as the association of central nervous system malignant tumors and familial colorectal cancer and has been reported to be both a dominant and recessive disorder. Homozygous and compound heterozygous mutations in APC, MLH1, MSH2, and PMS2 genes have been reported in five families. Here we describe a nonconsanguineous Pakistani family, including a son with lymphoma and colorectal cancer diagnosed at ages 5 and 8, respectively, and an 8-year-old daughter with glioblastoma multiforme. Both children had features of neurofibromatosis type 1 including atypical café au lait spots and axillary freckling without a family history consistent with neurofibromatosis type 1, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer. Mutational analysis was done for MLH1, MSH2, and MSH6 using denaturing high-performance liquid chromatography and sequencing of a blood sample from the daughter. A novel homozygous single base insertion mutation was identified (3634insT) resulting in a premature stop at codon 1,223 in exon 7 of the MSH6 gene. Both parents were found to be heterozygous for the 3634insT mutation. Microsatellite instability testing showed instability in the glioblastoma sample. We report here the first identification of a homozygous mutation in MSH6 in a family with childhood-onset brain tumor, lymphoma, colorectal cancer, and neurofibromatosis type 1 phenotype. Our findings support a role for MSH6 in Turcot syndrome and are consistent with an autosomal recessive mode of inheritance.
Retroperitoneoscopy-Assisted Cryoablation of Renal Tumors Using Multiple 1.5mm Ultrathin Cryoprobes: A Preliminary Report
Authors: Alexander Bachmann, Tullio Sulser, Christian Jayet, Stephen Wyler, Robin Ruszat, Oliver Reich, Thomas C. Gasser, Michael Siebels, Christian G. Stief, Roberto Casella
Journal: European Urology (2005)
Thyroid Hormone and Tricyclic Antidepressants in Resistant Depressions
Authors: BRIAN V. EARLE
Journal: American Journal of Psychiatry (1970)

The author conducted a study of 25 retarded depressed patients who previously responded inadequately to tricyclic antidepressants. Continuing the group on antidepressants, he also administered thyroid hormone. Fourteen showed an excellent response to the combination. He concludes that thyroid hormone potentiates the effects of the tricyclic antidepressants to some extent, but he suggests the need for further study in this area.
Association of Low Striatal Dopamine D<sub>2</sub>Receptor Availability With Nicotine Dependence Similar to That Seen With Other Drugs of Abuse
Authors: Christoph Fehr, Igor Yakushev, Nina Hohmann, Hans-Georg Buchholz, Christian Landvogt, Hanna Deckers, Alexandra Eberhardt, Marie Kläger, Michael N Smolka, Armin Scheurich, Thomas Dielentheis, Lutz G Schmidt, Frank Rösch, Peter Bartenstein, Gerhard Gründer, Mathias Schreckenberger
Journal: American Journal of Psychiatry (2008)

All drugs of abuse induce a phasic dopamine release within the striatum that does not undergo habituation. Prolonged substance consumption impairs the natural function of the mesolimbic dopamine system, as shown by a decrease in the availability of striatal dopamine 2 (D(2)) receptors in patients suffering from cocaine, heroin, amphetamine, and alcohol dependence. However, it is unclear whether similar changes can also be observed in heavy-smoking nicotine-dependent smokers.In vivo D(2)/D(3) receptor availability was determined with [ (18)F]fallypride positron emission tomography in 17 heavy-smoking nicotine-dependent subjects and in 21 age-matched never-smoking comparison subjects. The smokers were scanned twice: first, during a period of usual consumption and second, 24 hours after smoking cessation.Independent of the withdrawal status, the nicotine-dependent smokers displayed significantly less availability of D(2)/D(3) receptors within the bilateral putamen functionally covering parts of the dorsal striatum, as compared to the never-smoking subjects. Nicotine craving under the consumption condition correlated positively with D(2)/D(3) receptor availability within the ventral striatum but negatively with D(2)/D(3) receptor availability within the anterior cingulate and inferior temporal cortex.Similar to other types of substance abuse, nicotine dependence is associated with low availability of dorsal striatal D(2)/D(3) receptors. In contrast to previous findings on abstinent alcohol-dependent patients, nicotine craving seems to be maintained by a region-specific shift in D(2)/D(3) receptor availabilities, with higher availability within the ventral striatum but lower availability within the anterior cingulate and inferior temporal cortex.
PTH-076 University Hospital Southampton IBD Portal Pilot– An Innovative it Tool to Promote Patient Self-Care
Authors: M Naghibi, M Bettey, F Catherine, J Swabe, J Hunter, K Hamer, F J Cummings
Journal: Gut (2013)

<h3>Introduction</h3> Chronic disease management represents a big challenge to the NHS. The IBD standards specify the use of IT to support patient care and to optimise clinical management through data collection and audit. The development of innovative patient care pathways are required to meet these challenges as well as the Quality, Innovation, Productivity and Prevention (QIPP) agenda. ‘My Health Record’ is a secure web-based service built on the Microsoft HealthVault platform, which allows storage of health information from many sources in one secure online location. The IBD team and UHS IT department, in collaboration with web developers, GetReal, have designed this pilot website with the objective of improving patient access and care. <h3>Methods</h3> The IBD portal aims to provide an email based ‘Flareline’, record current and past medication history, inform patients of upcoming outpatient and endoscopy appointments, allow patient access to verified relevant investigation results, food/stool/health diaries and to provide tailored care plans with email and SMS reminders. We are taking advantage of existing innovative technologies, such as Smartphones capable of ‘Near Field Communication’ (NFC) and NFC enabled weight scales. These weight scales upload data directly to patient records, where aims and parameters are set, which alert the clinician to the progress of the patient. <h3>Results</h3> The pilot IBD portal was launched in September 2012. We have recruited n = 55 patients over 5 months, with n = 19 patients completing the registration process. The most commonly used function of the service to date has been the email ‘Flareline’ and messaging service. These enquiries were answered with in one day for ‘Flareline’ messages and 1.8 days for non-urgent messages. Three patients have been supplied with NFC enabled weight scales with all patients using the devices regularly. The data collected using the NFC devices has lead to reliable clinical data and timely changes in treatment, particularly dietetic input. <h3>Conclusion</h3> IBD is a chronic disease with a spectrum of clinical activity effecting quality of life and occurs in a significant proportion of patients in working age. The development of a web-based IBD portal is an innovative addition to IBD services with a potential to improve patient care and will lead to the development of new patient care pathways in collaboration with local care commissioning groups. We aim to improve cost effectiveness by reducing outpatient visits, reducing work load from phone based flareline enquiries and, provide more information on local IBD services for patients. Challenges to the IBD pilot so far have been to engage patients in this new model of care for chronic disease management. <h3>Disclosure of Interest</h3> None Declared.
Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke
Authors: Robert J. Adams, Marc I. Chimowitz, Joseph S. Alpert, Issam A. Awad, Manuel D. Cerqueria, Pierre Fayad, Kathryn A. Taubert
Journal: Circulation (2003)

HomeCirculationVol. 108, No. 10Coronary Risk Evaluation in Patients With Transient Ischemic Attack and Ischemic Stroke
Immunohistochemical analysis of the mammalian target of rapamycin signalling pathway in extramammary Paget’s disease
Authors: S. Chen, T. Nakahara, H. Uchi, S. Takeuchi, M. Takahara, M. Kido, L. Dugu, Y. Tu, Y. Moroi, M. Furue
Journal: British Journal of Dermatology (2009)

We have previously observed that persistent activation of the serine/threonine kinase, protein kinase B (AKT) is a frequent event in extramammary Paget's disease (EMPD). AKT promotes cell proliferation by its ability to coordinate mitogenic signalling with energy- and nutrient-sensing pathways that control protein synthesis through the atypical serine/threonine kinase, mammalian target of rapamycin (mTOR). CDK2, a member of the serine/threonine kinase family of cyclin-dependent kinases, is a key regulator of G(1)-S cell cycle progression, and has recently been shown to be one of the targets of AKT. The AKT-mTOR-p70 ribosomal protein S6 kinase (p70S6K) pathway has been described in some human malignancies, but not in EMPD.To investigate the immunohistochemical staining of the AKT-mTOR-p70S6K pathway in EMPD and to evaluate the relationships among the components.Samples of primary EMPD tissue were subjected to immunohistological staining with phosphorylated (p)-AKT, p-mTOR, p-4E-binding protein 1 (p-4EBP1), p-p70S6K/S6K1, p-ribosomal protein S6 (p-S6) and CDK2. Ten normal skin samples served as a control.Of the 32 EMPD tissue samples, 29, 27, 26, 29, 26 and 32 samples were positive for p-AKT, p-mTOR, p-4EBP1, p-p70S6K/S6K1, p-S6 and CDK2 staining, respectively. All these cell signalling molecules showed higher positivity in invasive EMPD than in EMPD in situ. There were significant correlations between p-AKT, p-mTOR, p-4EBP1, p-p70S6K/S6K1 and p-S6 and CDK2.The activation of the AKT-mTOR-p70S6K pathway may play an important role in the pathogenesis of EMPD. The high expression of the components of the pathway was highly correlated with CDK2 expression, suggesting that the AKT/mTOR pathway may induce the malignant transition through CDK2 in EMPD. The AKT-mTOR-p70S6K pathway might be a potential therapeutic target in EMPD.
Tropomodulin in rat cardiac muscle. Localization of protein is independent of messenger RNA distribution during myofibrillar development.
Authors: M A Sussman, S Sakhi, P Barrientos, M Ito, L Kedes
Journal: Circulation Research (1994)

Tropomodulin is a 40.6-kD protein that colocalizes with actin filament pointed ends in skeletal muscle. We report the sequence of two partial-length complementary DNA (cDNA) clones of rat cardiac tropomodulin that cover 90% of the coding region. The cDNA sequence is 90% conserved between human and rat, with the predicted amino acid sequence similarity even higher at 95%. Anti-tropomodulin antibodies label a single polypeptide with an apparent mobility of 43,000 in Western blot analysis of rat cardiac muscle. Immunofluorescence experiments using this anti-tropomodulin antibody result in labeling that is coincident with thin filament ends, as demonstrated by double localization with alpha-actinin antibody. Tropomodulin protein is organized into a sarcomeric staining pattern with the earliest appearance of myofibrils in rat cardiocytes. The localization of tropomodulin protein at or near thin filament ends led us to examine the distribution of tropomodulin messenger RNA (mRNA) during myofibrillar development in vitro. Fluorescent in situ hybridization experiments using tropomodulin cDNA probe in cardiocytes that have been cultured for 3 to 5 days show a distribution of large mRNA patches. The cytoplasmic location of tropomodulin mRNA at this time, which bears no relation to the developed myofibrils, suggests that tropomodulin protein is targeted to thin filament ends rather than using localized translational machinery. However, the distribution of tropomodulin mRNA in cultured cardiocytes changes over the next 2 weeks from large perinuclear patches to small concentrations arranged along myofibrils throughout the cell. The reorganization of tropomodulin mRNA throughout the cardiocyte appears to be distinct from the pattern of glyceraldehyde-3-phosphate dehydrogenase mRNA within the same time period. Increasing intracellular density of myofibrils within developing cardiocytes may lead to redistribution of selected mRNAs for localized translation.
Rituximab Therapy for Patients With Newly Diagnosed, Advanced-Stage, Follicular Grade I Non-Hodgkin's Lymphoma: A Phase II Trial in the North Central Cancer Treatment Group
Authors: Thomas E. Witzig, Allen M. Vukov, Thomas M. Habermann, Susan Geyer, Paul J. Kurtin, William R. Friedenberg, William L. White, Haji I. Chalchal, Patrick J. Flynn, Thomas R. Fitch, Debra A. Welker
Journal: Journal of Clinical Oncology (2005)

Patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkin's lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy. The goals of this study were to assess the overall response rate (ORR) to rituximab in this patient population and to determine the time-to-progression (TTP) and time-to-subsequent-chemotherapy (TTSC).Eligible patients had untreated follicular grade 1 NHL, and measurable stage III/IV disease. Patients received rituximab 375 mg/m(2) intravenous weekly x 4 doses and were then followed for response and progression; no maintenance therapy was provided.Thirty-seven patients were accrued; one patient was ineligible. The median age was 59 years (range, 29 to 83 years). Six patients (18%) had elevated lactate dehydrogenase levels. The ORR was 72%, with 36% complete remissions. Fourteen (39%) of 36 patients remain in unmaintained remission, two died without disease progression, and three died with disease progression. Twenty (56%) of 36 patients have disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached). Eighteen patients have subsequently been treated with chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached). Patients with a high lactate dehydrogenase level had a lower ORR of 33% and a short TTP of only 6 months.Rituximab can be safely administered to patients with advanced-stage follicular grade 1 NHL with efficacy and minimal toxicity. This therapy is highly active and offers an acceptable alternative to observation in this patient population. Patients with high LDH should not be considered for rituximab monotherapy.
Function of the anal sphincters after chronic radiation injury.
Authors: J S Varma, A N Smith, A Busuttil
Journal: Gut (1986)

Anorectal manometry was done in 10 men with chronic radiation proctitis and symptoms of urgency, frequency, and occasional incontinence of faeces. They were compared with 10 asymptomatic age and sex-matched controls. The maximum resting anal canal pressure and the physiological sphincter length were significantly lower (p less than 0.01) in the irradiated group. The rectosphincteric reflex was absent in one patient and showed abnormalities of recovery in four others, who had received radiotherapy. The squeeze pressure of the external sphincter was not significantly different. These results indicate that dysfunction of the internal anal sphincter may contribute to patients9 anorectal symptoms after pelvic radiotherapy. Histological evidence suggests that damage to the myenteric plexus is mainly responsible. The manometric function of the external sphincter remains relatively unaffected.
Functional Identification of Cancer-Specific Methylation of <i>CDO1</i>, <i>HOXA9</i>, and <i>TAC1</i> for the Diagnosis of Lung Cancer
Authors: John Wrangle, Emi Ota Machida, Ludmila Danilova, Alicia Hulbert, Noreli Franco, Wei Zhang, Sabine C. Glöckner, Mathewos Tessema, Leander Van Neste, Hariharan Easwaran, Kornel E. Schuebel, Julien Licchesi, Craig M. Hooker, Nita Ahuja, Jun Amano, Steven A. Belinsky, Stephen B. Baylin, James G. Herman, Malcolm V. Brock
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Non–small cell lung cancer (NSCLC) is the leading cause of cancer mortality in the world. Novel diagnostic biomarkers may augment both existing NSCLC screening methods as well as molecular diagnostic tests of surgical specimens to more accurately stratify and stage candidates for adjuvant chemotherapy. Hypermethylation of CpG islands is a common and important alteration in the transition from normal tissue to cancer. Experimental Design: Following previously validated methods for the discovery of cancer-specific hypermethylation changes, we treated eight NSCLC cell lines with the hypomethylating agent deoxyazacitidine or trichostatin A. We validated the findings using a large publicly available database and two independent cohorts of primary samples. Results: We identified &amp;gt;300 candidate genes. Using The Cancer Genome Atlas (TCGA) and extensive filtering to refine our candidate genes for the greatest ability to distinguish tumor from normal, we define a three-gene panel, CDO1, HOXA9, and TAC1, which we subsequently validate in two independent cohorts of primary NSCLC samples. This three-gene panel is 100% specific, showing no methylation in 75 TCGA normal and seven primary normal samples and is 83% to 99% sensitive for NSCLC depending on the cohort. Conclusion: This degree of sensitivity and specificity may be of high value to diagnose the earliest stages of NSCLC. Addition of this three-gene panel to other previously validated methylation biomarkers holds great promise in both early diagnosis and molecular staging of NSCLC. Clin Cancer Res; 20(7); 1856–64. ©2014 AACR.
Trends in Inflammatory Breast Carcinoma Incidence and Survival: The Surveillance, Epidemiology, and End Results Program at the National Cancer Institute
Authors: Kenneth W. Hance, William F. Anderson, Susan S. Devesa, Heather A. Young, Paul H. Levine
Journal: JNCI Journal of the National Cancer Institute (2005)

Background: Inflammatory breast carcinoma (IBC) appears to be a clinicopathologic entity distinct from noninflammatory locally advanced breast cancer (LABC). We examined incidence and survival trends for IBC in Surveillance, Epidemiology, and End Results (SEER) Program data with a case definition designed to capture many of its unique clinical and pathologic characteristics. Methods: We analyzed breast cancer cases diagnosed in the SEER 9 Registries ( n = 180 224), between 1988 and 2000. Breast cancer cases were categorized using SEER's "Extent of Disease" codes in combination with International Classification of Diseases for Oncology morphology code 8530/3 and classified as IBC ( n = 3648), LABC ( n = 3636), and non-T4 breast cancer ( n = 172 940). We compared changes in incidence rates over 3-year intervals by breast cancer subtype and race using SEER*Stat. Survival differences by breast cancer subtype and race were assessed using Kaplan–Meier curves and log-rank statistics. All statistical tests were two-sided. Results: Between 1988 and 1990 and 1997 and 1999, IBC incidence rates (per 100 000 woman-years) increased from 2.0 to 2.5 ( P <.001), whereas those for LABC declined (2.5 to 2.0, P = .0025), as did those for non-T4 breast cancer (108 to 101, P = .0084). IBC incidence rates were statistically significantly higher in black women (3.1) than in white women (2.2) during the study period ( P <.001). Women diagnosed with IBC had statistically significantly poorer survival than women with either LABC or non-T4 breast cancer (log-rank test, P <.001). Median survival of women with IBC (2.9 years) was statistically significantly shorter than that of women with LABC (6.4 years; P <.0001) or non-T4 breast cancer (>10 years, P <.0001). Black women with IBC or LABC had poorer survival than white women with IBC or LABC, respectively (log-rank test, P <.001). Conclusions: Throughout the 1990s, IBC incidence rose, and survival improved modestly. Substantial racial differences were noted in age at diagnosis, age-specific incidence rates, and survival outcomes.