tbuckley/cabot-search huggingface dataset:
PWE-109 Should CT colonoscopy replace flexible sigmoidoscopy examination as first line investigation in patients with suspected colorectal cancer?
Authors: U D Simoniuk, A Milewska, C Kiire
Journal: Gut (2012)

<h3>Introduction</h3> It is recommended that all patients undergoing barium enema have a flexible sigmoidoscopy to exclude disease in rectum and sigmoid colon. With the introduction of CT colonoscopy (CT colon) is sigmoidoscopy still required for the investigation of patients with suspected colorectal cancer (CRC).<sup>1</sup> We reviewed CT colon and flexible sigmoidoscopy results in our patients who underwent both procedures with a view to answering this question. <h3>Methods</h3> The findings of CT colon in 520 consecutive patients were reviewed by a GI radiologist blinded to the findings at flexible sidmoidoscopy. The mean age of the population was 65 years old. Patients with inadequate bowel preparation for flexible sigmoidoscopy, colonoscopy, polypectomy, abnormal MRI or CT colon as first line investigation and more than 6 months period between CT colon and flexible sigmoidoscopy were excluded. Statistical analysis was performed with χ<sup>2</sup> and Fisher test. <h3>Results</h3> 332 patients were excluded for the reasons stated above. 188 patients were analysed. In 88% of these there was concordance between the results of CT colon and flexible sigmoidoscopy. Statistically significant (p&lt;0.001) association was shown between detecting cancer by flexible sigmoidoscopy vs CT colon. The sensitivity and specificity of flexible sigmoidoscopy was 74% and 99% respectively [ppv—0.93, npv—0.94]. Flexible sigmoidoscopy did not identify six cancers which were revealed on CT colon. CT colon did not detect two cancers due to collapse colon and further investigation was recommended. There was statistical significant (p&lt;0.05) association between bowel symptoms such as PR bleeding and iron deficiency anaemia and the diagnosis of bowel cancer in patients undergoing flexible sigmoidoscopy. <h3>Conclusion</h3> CT colon should replace flexible sigmoidoscopy especially in elderly patients as first line investigation. Flexible sigmoidoscopy still has a role in those patients who found on CT colon to have a collapse left colon. <h3>Competing interests</h3> None declared. <h3>Reference</h3> 1. <b>NICE clinical guideline</b>. <i>“The Diagnosis and Management of Colorectal Cancer”</i>. Issued: November 2011.
Clozapine-Associated Elevation in Serum Triglycerides
Authors: B D Gaulin, J S Markowitz, C F Caley, L A Nesbitt, R L Dufresne
Journal: American Journal of Psychiatry (1999)

OBJECTIVE: This study was conducted to determine serum lipid level changes in patients who received clozapine or haloperidol. METHOD: Medical records of 222 inpatients treated with clozapine or haloperidol were reviewed. Age, weight, gender, daily antipsychotic dose, total cholesterol level, serum triglyceride level, and concurrent medications were recorded. RESULTS: Clozapine-treated men had significantly higher follow-up serum triglyceride concentrations over baseline than did haloperidol-treated men. Female patients experienced serum triglyceride level elevations regardless of antipsychotic treatment. Changes in total cholesterol levels were not significantly different between treatment groups. CONCLUSIONS: An increase in serum triglyceride levels occurred in clozapine-treated patients; screening for serum triglyceride elevations may be warranted before treatment with clozapine.
Troponin I protein kinase C phosphorylation sites and ventricular function
Authors: G MACGOWAN
Journal: Cardiovascular Research (2004)

Objective:Cardiac Troponin I (cTnI) phosphorylation by protein kinase C (PKC) results in a reduction of maximal actomyosin ATPase activity, an effect that is more marked at higher levels of calcium (Ca2+) and is likely to reduce active force development. We postulated that there would be greater Ca2+-dependent changes in ventricular function in hearts of cTnI transgenic (TG) mice expressing mutant troponin I lacking PKC sites compared to wild-type (WT). Methods:We studied left ventricular function in isolated perfused hearts over a wide range of left ventricular volumes (Frank-Starling relationships) and mechanical restitution at three levels of perfusate Ca2+ (1.5, 2.5, and 3.5 mM). Manganese-enhanced magnetic resonance imaging (MRI) was used to study in-vivo sarcolemmal Ca2+ influx. The phosphorylation status of cTnI was examined by western blot analysis. Results:Systolic contractile function in TG mice was altered in a calcium-dependent manner such that ventricular contractility was significantly greater in TG mice only at 3.5 mM perfusate Ca2+. The relaxation process and passive mechanical properties were unaltered in TG mice. Mechanical restitution parameters were abnormal in TG mice only at 1.5 mM perfusate Ca2+. In-vivo MRI data demonstrated up to 48% reduction in Mn2+-induced contrast enhancement, indicating reduced sarcolemmal Ca2+ influx. Western blot analysis indicated increased cTnI phosphorylation in TG mice. Conclusions:(1) TG mice exhibit calcium-dependent positive inotropy without slowed relaxation and this phenotype is mitigated by concomitant (compensatory) changes of reduced intracellular Ca2+ and increased phosphorylation of remaining cTnI sites. (2) The contractile phenotype in TG mice can be interpreted as an amplification of the normal response to changes in cellular Ca2+ observed in WT mice. Thus, PKC phosphorylation sites on cTnI play a role in attenuating contractile responses to changes in intracellular Ca2+.
Chemokine Expression in Melanoma Metastases Associated with CD8+ T-Cell Recruitment
Authors: Helena Harlin, Yuru Meng, Amy C. Peterson, Yuanyuan Zha, Maria Tretiakova, Craig Slingluff, Mark McKee, Thomas F. Gajewski
Journal: Cancer Research (2009)

Abstract Despite the frequent detection of circulating tumor antigen–specific T cells, either spontaneously or following active immunization or adoptive transfer, immune-mediated cancer regression occurs only in the minority of patients. One theoretical rate-limiting step is whether effector T cells successfully migrate into metastatic tumor sites. Affymetrix gene expression profiling done on a series of metastatic melanoma biopsies revealed a major segregation of samples based on the presence or absence of T-cell–associated transcripts. The presence of lymphocytes correlated with the expression of defined chemokine genes. A subset of six chemokines (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10) was confirmed by protein array and/or quantitative reverse transcription-PCR to be preferentially expressed in tumors that contained T cells. Corresponding chemokine receptors were found to be up-regulated on human CD8+ effector T cells, and transwell migration assays confirmed the ability of each of these chemokines to promote migration of CD8+ effector cells in vitro. Screening by chemokine protein array identified a subset of melanoma cell lines that produced a similar broad array of chemokines. These melanoma cells more effectively recruited human CD8+ effector T cells when implanted as xenografts in nonobese diabetic/severe combined immunodeficient mice in vivo. Chemokine blockade with specific antibodies inhibited migration of CD8+ T cells. Our results suggest that lack of critical chemokines in a subset of melanoma metastases may limit the migration of activated T cells, which in turn could limit the effectiveness of antitumor immunity. [Cancer Res 2009;69(7):3077–85]
Molecular Karyotypes of Hodgkin and Reed–Sternberg Cells at Disease Onset Reveal Distinct Copy Number Alterations in Chemosensitive versus Refractory Hodgkin Lymphoma
Authors: Marilyn L. Slovak, Victoria Bedell, Ya-Hsuan Hsu, Dolores B. Estrine, Norma J. Nowak, Maria L. Delioukina, Lawrence M. Weiss, David D. Smith, Stephen J. Forman
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To determine the recurring DNA copy number alterations (CNA) in classical Hodgkin lymphoma (HL) by microarray-based comparative genomic hybridization (aCGH) using laser capture microdissected CD30+ Hodgkin and Reed–Sternberg (HRS) cells. Experimental Design: Archived tissues from 27 CD30+ HL plus control samples were analyzed by DNA microarrays. The HL molecular karyotypes were compared with the genomic profiles of germinal center B cells and treatment outcome (chemotherapy responsive vs. primary refractory disease). Results: Gains and losses observed in more than 35% of HL samples were localized to 22 and 12 chromosomal regions, respectively. Frequent gains (&amp;gt;65%) were associated with growth and proliferation, NF-κB activation, cell-cycle control, apoptosis, and immune and lymphoid development. Frequent losses (&amp;gt;40%) observed encompassed tumor suppressor genes (SPRY1, NELL1, and ID4, inhibitor of DNA binding 4), transcriptional repressors (TXNIP, thioredoxin interacting protein), SKP2 (S-phase kinase-associated protein 2; ubiquitin ligase component), and an antagonist of NF-κB activation (PPARGC1A). In comparison to the germinal center profiles, the most frequent imbalances in HL were losses in 5p13 (AMACR, GDNF, and SKP2), and gains in 7q36 (SHH, sonic hedgehog homolog) and 9q34 (ABL1, CDK9, LCN2, and PTGES). Gains (&amp;gt;35%) in the HL chemoresponsive patients housed genes known to regulate T-cell trafficking or NF-κB activation (CCL22, CX3CL1, CCL17, DOK4, and IL10), whereas the refractory samples showed frequent loss of 4q27 (interleukin; IL21/IL2) and 17p12, and gain of 19q13.3 (BCL3/RELB). Conclusion: We identified nonrandom CNAs in the molecular karyotypes of classical HL. Several recurring genetic lesions correlated with disease outcome. These findings may be useful prognostic markers in the counseling and management of patients and for the development of novel therapeutic approaches in primary refractory HL. Clin Cancer Res; 17(10); 3443–54. ©2011 AACR.
Nonsecretory multiple myeloma
Authors: Robert Dreicer, Raymond Alexanian
Journal: American Journal of Hematology (1982)

Abstract The clinical features and disease course of 29 consecutive multiple myeloma patients without monoclonal globulins are described. This variant accounted for 4.7% of all patients with this disease referred over a 17 year time span. Despite bone marrow plasmacytosis and multiple bone lesions in all, hemoglobin levels were less frequently depressed and immunoglobulin values more frequently preserved in comparison with typical myeloma patients. A low tumor mass was defined in 69%, in comparison with 24% of those with evidence of myeloma protein production. Such earlier disease contributed to the long median survival of 39 months in these patients, a duration about 1 year longer than that of typical patients.
Multiple activities of a cloned cell line mediating natural killer cell function.
Authors: G Nabel, L R Bucalo, J Allard, H Wigzell, H Cantor
Journal: The Journal of Experimental Medicine (1981)

A special class of immunologic cells can lyse or damage a variety of target cells, notably malignant cells in vitro. These cells have been called natural killer (NK) cells because lysis does not require deliberate immunization by tumor cells. Although these cells can be distinguished from conventional T cells, B cells, and phagocytic cells, they have been difficult to define. We describe a representative cloned cell line that was obtained by cloning Ig -Ly-5+ cells from spleen. This clone, Cl.Ly-1-2-NK-1+/11, displays Thy-1, Ly-5, Qat-4, Qat-5 and NK-1 cell surface antigens and lyses the NK-sensitive YAC-1 lymphoma cells, but does not lyse RL-12 cells, an NK-resistant lymphoma. In addition, this clone lysed the P815 mastocytoma, EL4 lymphoma, and lipopolysaccharide-activated B lymphocyte targets. This cloned population therefore combined information for a unique display of cell surface antigens and specialized function similar to "activated" NK cells. Because this cloned population forms conjugates with susceptible but not resistant target cells, it may prove useful to identify the structure of cell surface molecules that recognize foreign cells. Finally, cells of this clone also specificity lysed target cells coated by antibodies to determinants on the target cell surface, demonstrating that a single cloned cell population can mediate two specialized immunologic functions: antibody-dependent cellular cytotoxicity and NK cell lysis.
Loss of DNA Polymerase ζ Enhances Spontaneous Tumorigenesis
Authors: John P. Wittschieben, Vaishali Patil, Veronika Glushets, Lisa J. Robinson, Donna F. Kusewitt, Richard D. Wood
Journal: Cancer Research (2010)

Abstract Mammalian genomes encode at least 15 distinct DNA polymerases, functioning as specialists in DNA replication, DNA repair, recombination, or bypass of DNA damage. Although the DNA polymerase ζ (polζ) catalytic subunit REV3L is important in defense against genotoxins, little is known of its biological function. This is because REV3L is essential during embryogenesis, unlike other translesion DNA polymerases. Outstanding questions include whether any adult cells are viable in the absence of polζ and whether polζ status influences tumorigenesis. REV3L-deficient cells have properties that could influence the development of neoplasia in opposing ways: markedly reduced damage-induced point mutagenesis and extensive chromosome instability. To answer these questions, Rev3L was conditionally deleted from tissues of adult mice using MMTV-Cre. Loss of REV3L was tolerated in epithelial tissues but not in the hematopoietic lineage. Thymic lymphomas in Tp53−/− Rev3L conditional mice occurred with decreased latency and higher incidence. The lymphomas were populated predominantly by Rev3L-null T cells, showing that loss of Rev3L can promote tumorigenesis. Remarkably, the tumors were frequently oligoclonal, consistent with accelerated genetic changes in the absence of Rev3L. Mammary tumors could also arise from Rev3L-deleted cells in both Tp53+/+ and Tp53+/− backgrounds. Mammary tumors in Tp53+/− mice deleting Rev3L formed months earlier than mammary tumors in Tp53+/− control mice. Prominent preneoplastic changes in glandular tissue adjacent to these tumors occurred only in mice deleting Rev3L and were associated with increased tumor multiplicity. Polζ is the only specialized DNA polymerase yet identified that inhibits spontaneous tumor development. Cancer Res; 70(7); 2770–8
Probucol Protects Against Smooth Muscle Cell Proliferation by Upregulating Heme Oxygenase-1
Authors: Yi-Mo Deng, Ben J. Wu, Paul K. Witting, Roland Stocker
Journal: Circulation (2004)

Evidence suggests that induction of heme oxygenase-1 (HO-1) inhibits proliferation of vascular smooth muscle cells and intimal thickening after arterial injury, and therapeutic molecules induce HO-1. Probucol is the only oral drug that inhibits restenosis in humans and intimal thickening in animals, although its underlying mechanism remains unclear.Aortas were harvested from New Zealand White rabbits fed normal or 0.75% (wt/wt) probucol-fortified chow, with or without endothelial denudation of the abdominal aorta on day 21, and analyzed for heme oxygenase and apoptosis. Uninjured aortas were harvested on day 21 and balloon-injured aortas on days 22 and 25. Probucol significantly increased mRNA of HO-1 assessed by real-time PCR and HO activity in aortas at all time points. Probucol also enhanced apoptosis of medial cells in the injured aorta, as evidenced by the TUNEL assay. Furthermore, probucol (100 micromol/L) increased HO-1 mRNA and HO activity when added to rabbit aortic smooth muscle cells (RASMCs) cultured in serum-free medium for 24 hours. Induction of HO-1 mRNA was inhibited by actinomycin D and was associated with inhibition of RASMC proliferation. This probucol-induced increase in HO-1 mRNA and inhibition of RASMC proliferation was prevented by the HO inhibitor Sn(IV) protoporphyrin or transfection with small interference RNA (siRNA) to knockdown HO-1, but not by inactive Cu(II) protoporphyrin or scrambled siRNA.Probucol induces HO-1, and this contributes to the inhibition of vascular SMC proliferation. This novel finding may explain how probucol inhibits restenosis and highlights HO-1 as a target for therapeutic intervention against occlusive vascular disease.
Different Faces of the Heme-Heme Oxygenase System in Inflammation
Authors: Frank A. D. T. G. Wagener, Hans-Dieter Volk, Dean Willis, Nader G. Abraham, Miguel P. Soares, Gosse J. Adema, Carl G. Figdor
Journal: Pharmacological Reviews (2003)

The heme-heme oxygenase system has recently been recognized to possess important regulatory properties. It is tightly involved in both physiological as well as pathophysiological processes, such as cytoprotection, apoptosis, and inflammation. Heme functions as a double-edged sword. In moderate quantities and bound to protein, it forms an essential element for various biological processes, but when unleashed in large amounts, it can become toxic by mediating oxidative stress and inflammation. The effect of this free heme on the vascular system is determined by extracellular factors, such as hemoglobin/heme-binding proteins, haptoglobin, albumin, and hemopexin, and intracellular factors, including heme oxygenases and ferritin. Heme oxygenase (HO) enzyme activity results in the degradation of heme and the production of iron, carbon monoxide, and biliverdin. All these heme-degradation products are potentially toxic, but may also provide strong cytoprotection, depending on the generated amounts and the microenvironment. Pre-induction of HO activity has been demonstrated to ameliorate inflammation and mediate potent resistance to oxidative injury. A better understanding of the complex heme-heme
Perforated peptic ulcer over 56 years. Time trends in patients and disease characteristics.
Authors: C Svanes, H Salvesen, L Stangeland, K Svanes, O Soreide
Journal: Gut (1993)

Perforated gastroduodenal ulcer was studied in 1483 patients in the Bergen area during the years 1935-90 to discover time trends in age and sex, disease characteristics, treatment, and outcome. The male:female ratio fell from 10:1 to 1.5:1, median age increased from 41 to 62 years. Most perforations were found in the duodenum in 1935-64, and in the pyloric and praepyloric area in 1965-90. There was a 10% occurrence of gastric ulcers throughout the study period. Ulcer site was related to age (more gastric and less duodenal perforations with increasing age) and sex (more pyloric and less duodenal ulcers among women). There were twice as many perforations in the evening compared with the early morning. The diurnal variation was more pronounced for duodenal and pyloric than for gastric and praepyloric perforations. Circadian and seasonal variation of ulcer perforation did not change during the 56 years studied. Treatment delay increased from median five hours to median nine hours. Infective complications and mortality fell with the introduction of antibiotics around 1950. General complications has increased in recent years because of the increase of elderly patients. Among patients who died, the proportion with associated disease rose from 27 to 85% during the study period.
Arthritis of the middle ear in ankylosing spondylitis.
Authors: E Pascual-Gomez, J J Lopez-Rico
Journal: Annals of the Rheumatic Diseases (1985)

Arthritis of the middle ear in ankylosing spondylitis SIR, We have read with interest the paper by Magaro, Ceresia, and Frustaci on arthritis of the middle ear in ankylosing spondylitis
A community study of snoring and sleep-disordered breathing. Symptoms.
Authors: L G Olson, M T King, M J Hensley, N A Saunders
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Four hundred forty-one subjects 34 to 69 yr of age were recruited from a random sample of the community. The sample was biased in favor of men, snorers, and subjects with subjective sleep complaints. They answered a questionnaire and were monitored in their homes for sleep-disordered breathing (SDB). This report concerns the presence of symptoms associated with the obstructive sleep apnea (OSA) syndrome in the subjects with SDB detected in this community sample. Most of the symptoms commonly recognized as occurring in OSA were associated with SDB in our sample: snoring that disturbed the sleep of other persons, reports of apnea, reports of gasping or choking sounds during sleep, and finding the bedclothes in disarray in the mornings had significant univariate associations with SDB. Nocturnal choking and morning headache were negatively associated with SDB. Excessive daytime somnolence (EDS) was reported by 41% of those with SDB, but it was also reported by 37% of snorers without SDB and by 37% of nonsnorers. We conclude that the symptoms seen in clinic patients with OSA also occur in subjects with SDB who have not presented for medical attention. Enumeration of these symptoms by questionnaire, however, is a poor test for OSA in the community. EDS was reported by a higher than expected proportion of subjects not affected by SDB, suggesting that causes of self-reported EDS other than SDB may be common.
A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer
Authors: Tanguy Y. Seiwert, Philip P. Connell, Ann M. Mauer, Philip C. Hoffman, Christopher M. George, Livia Szeto, Ravi Salgia, Katherine E. Posther, Binh Nguyen, Daniel J. Haraf, Everett E. Vokes
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy. Experimental Design: Patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m2); regimen 2 was pemetrexed (500 mg/m2) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower). Results: Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m2). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m2; AUC = 6); grade 3/4 leukopenia (4 of 12 patients) was the main hematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed. When systemically active chemotherapy doses were reached, further dose escalation was discontinued, and a phase II dose-range was established (pemetrexed 500 mg/m2 and carboplatin AUC = 5-6). Conclusions: The combination of pemetrexed (500 mg/m2) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.