tbuckley/cabot-search huggingface dataset:
Selected Toll-like Receptor Ligands and Viruses Promote Helper-Independent Cytotoxic T Cell Priming by Upregulating CD40L on Dendritic Cells
Authors: Susan Johnson, Yifan Zhan, Robyn M. Sutherland, Adele M. Mount, Sammy Bedoui, Jamie L. Brady, Emma M. Carrington, Lorena E. Brown, Gabrielle T. Belz, William R. Heath, Andrew M. Lew
Journal: Immunity (2009)
A Tale of Two Tumors: Treating Pancreatic and Extrapancreatic Neuroendocrine Tumors
Authors: Daniel M. Halperin, Matthew H. Kulke, James C. Yao
Journal: Annual Review of Medicine (2014)

Despite their perceived rarity, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rising in incidence and prevalence. The biology, natural history, and therapeutic options for GEP-NETs are heterogeneous: NETs arising in the pancreas can be distinguished from those arising elsewhere in the gastrointestinal tract, and therapy is dichotomized between these two groups. Somatostatin analogues are the mainstay of oncologic management of bowel NETs; everolimus, streptozocin, and sunitinib are approved to treat pancreatic NETs. There are significant differences in molecular genetics between pancreatic and extrapancreatic NETs, and studies are evaluating whether additional NET patients may benefit from targeted agents. We discuss the distinguishing features of these two groups of tumors, as well as the therapeutic implications of the distinction. We also examine the evolving therapeutic landscape and discuss the likelihood that treatment will be developed independently for pancreatic and extrapancreatic gastrointestinal NETs, with novel therapeutics effective for newly identified pathologically or molecularly defined subgroups.
High detection rate of adenomas in familial colorectal cancer
Authors: A. E. van der Meulen-de Jong, H. Morreau, M. C. J. M. Becx, L. F. S. J. Crobach, M. v. Haastert, W. R. t. Hove, J. H. Kleibeuker, M. A. C. Meijssen, F. M. Nagengast, M. C. M. Rijk, J. M. J. I. Salemans, A. Stronkhorst, H. A. R. E. Tuynman, J. Vecht, M. L. Verhulst, W. H. de Vos tot Nederveen Cappel, H. Walinga, O. K. Weinhardt, B. D. Westerveld, A. M. C. Witte, H. J. Wolters, H. F. A. Vasen
Journal: Gut (2010)

<h3>Background and aims</h3> Subjects with one first-degree relative (FDR) with colorectal cancer (CRC) &lt;50 years old or two FDRs with CRC have an increased risk for CRC (RR 4–6). Current guidelines recommend colonoscopic surveillance of such families. However, information about the yield of surveillance is limited. The aim of the present study was to evaluate the outcome of surveillance and to identify risk factors for the development of adenomas. <h3>Patients and methods</h3> Subjects were included if they fulfilled the following criteria: asymptomatic subjects aged between 45 and 65 years, with one FDR with CRC &lt;50 years old (group A) or two FDRs with CRC diagnosed at any age (group B). Subjects with a personal history of inflammatory bowel disease or colorectal surgery were excluded. <h3>Results</h3> A total of 551 subjects (242 male) met the selection criteria. Ninety-five subjects with a previous colonoscopy were excluded. Two of 456 remaining subjects (0.4%) were found to have a colorectal tumour (one CRC and one carcinoid). Adenomas were detected in 85 (18.6%) and adenomas with advanced pathology in 37 subjects (8.1%). 30 subjects (6.6%) had multiple (&gt;1) adenomas. Men were more often found to have an adenoma than women (24% vs 14.3%; p=0.01). Adenomas were more frequent in group B compared with group A (22.0% vs 15.6%; p=0.09). <h3>Conclusion</h3> The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population.
Selective immediate responders to amoxicillin and clavulanic acid tolerate penicillin derivative administration after confirming the diagnosis
Authors: N. Blanca‐Lopez, D. Perez‐Alzate, F. Ruano, M. Garcimartin, V. de la Torre, C. Mayorga, M. L. Somoza, J. Perkins, M. Blanca, M. G. Canto, M. J. Torres
Journal: Allergy (2015)

An increasing number of patients show immediate selective hypersensitivity reactions to clavulanic acid (CLV) and amoxicillin (AX), probably due to their increased prescription. The maintenance of this response should be established.To assess that the immediate hypersensitivity selective response to AX or to CLV is maintained after repeated administration of penicillin G (PG)/penicillin V (PV) and AX.Patients with proven immediate hypersensitivity to AX (Group A) or CLV (Group B) were included. Diagnosis was performed using skin tests with major and minor determinants of PG (PPL/MDM), AX and CLV and by drug provocation test (DPT) if required. Selectivity was established by confirming tolerance to PG/PV (Group A) and to PG/PV and AX (Group B). The maintenance of the selective response was verified by repeating DPT, 15 days after the initial investigation, with the same procedure.Of 51 patients, 78% belonged to Group A and 22% to Group B. Most had anaphylaxis. In Group A, 72% were skin test positive; 28% required DPT. In Group B, 63% were skin test positive; 37% required DPT. Only two AX-selective cases developed positive responses after re-provocation with PG/PV. No cases selective for CLV developed a positive response to PG, PV or AX.The selective response to AX appears consistent, and a response to penicillin determinants only develops in a minority of cases. For the case of CLV, the selective response appears not to be modified by exposure to penicillin determinants, meaning that patients with CLV allergy can take penicillin derivatives safely.
C-Reactive Protein and Prediction of Coronary Heart Disease and Global Vascular Events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)
Authors: Naveed Sattar, Heather M. Murray, Alex McConnachie, Gerard J. Blauw, Edward L.E.M. Bollen, Brendan M. Buckley, Stuart M. Cobbe, Ian Ford, Allan Gaw, Michael Hyland, J. Wouter Jukema, Adriaan M. Kamper, Peter W. Macfarlane, Michael B. Murphy, Chris J. Packard, Ivan J. Perry, David J. Stott, Brian J. Sweeney, Cillian Twomey, Rudi G.J. Westendorp, James Shepherd
Journal: Circulation (2007)

The role of C-reactive protein (CRP) in predicting vascular events and response to statin therapy remains uncertain. Additional large prospective studies are required.Baseline CRP was related to risk over 3.2 years for primary a combined end point (definite or suspected death from coronary heart disease, nonfatal myocardial infarction, and fatal or nonfatal stroke; n=865 events) and secondary (coronary heart disease events or stroke alone) and tertiary (stroke plus transient ischemic attack) end points in the Prospective Study of Pravastatin in the Elderly at Risk (n=5804 men and women; age, 70 to 82 years). CRP levels were higher in subjects who had a subsequent primary end-point event compared with those who did not (geometric mean; 3.64 mg/L [SD, 3.08 mg/L] versus 3.01 mg/L [SD, 3.05 mg/L]; P<0.0001). CRP correlated positively with body mass index and smoking status and negatively with high-density lipoprotein cholesterol. The unadjusted hazard ratio for the primary end point was 1.48 (95% CI, 1.26 to 1.74) in a comparison of top and bottom thirds for CRP, falling to 1.36 (95% CI, 1.15 to 1.61) with adjustment for established predictors and body mass index. Similar results were obtained for other end points or when results were examined separately by history of vascular disease. However, baseline CRP added minimally to risk prediction beyond conventional predictors and did not relate to the magnitude of pravastatin benefit.Elevated CRP minimally enhances cardiovascular disease prediction beyond established vascular risk factors and does not predict response to statin therapy in elderly subjects at risk. These data suggest that CRP has limited clinical value in cardiovascular disease risk stratification or predicting response to statin therapy in elderly people.
The challenge of follow-up in narrowband ultraviolet B phototherapy
Authors: B.L. Diffey, P.M. Farr
Journal: British Journal of Dermatology (2007)

The use of narrowband ultraviolet (UV) B phototherapy to treat psoriasis and other disorders has increased markedly since the TL-01 lamps were introduced in the 1980s. While broadband UVB phototherapy has generally been considered to be a relatively safe treatment, some concern has been raised about the potential increased skin cancer risk with narrowband UVB.The likelihood of a patient who is free of nonmelanoma skin cancer (NMSC) at the start of phototherapy developing a malignancy after a certain follow-up period will be dependent not only on the carcinogenic potential of the treatment but also on the age-conditional probability of natural occurrence. We were interested to explore the potential difficulty of designing studies to separate these two events. Methods Mathematical models were developed that combined age-conditional probabilities of developing NMSC due to natural causes with the risk of inducing these cancers from narrowband UVB phototherapy in order to estimate the excess number of cancers resulting from this therapeutic intervention in a cohort of patients.Within-department studies will be most unlikely to demonstrate that the number of NMSCs observed in follow-up studies is significantly different from that expected in an untreated population, even for a follow-up period of 20 years.Determination of the carcinogenic potential associated with narrowband UVB will require large multicentre studies typically involving several thousand new patients per year and followed up for 10 years or more.
Intrapulmonary growth and dissemination of an avirulent strain of Cryptococcus neoformans in mice depleted of CD4+ or CD8+ T cells.
Authors: J O Hill, A G Harmsen
Journal: The Journal of Experimental Medicine (1991)

The contribution of T lymphocyte subpopulations to intrapulmonary and systemic resistance against an opportunistic strain of Cryptococcus neoformans was examined. It was found that C. neoformans was destroyed when introduced into the lungs of normal mice, but disseminated to the brains of mice treated with an antibody that depleted them of CD4+ T cells. Depletion of either CD8+ or CD4+ T cells impaired the ability of the host to clear the yeast from the lung. These results, together with the observation that CD8+ T cells accumulate in the lungs of CD4+ T cell-deficient mice, suggest that CD8+ T cells play an important role in resistance to C. neoformans infection acquired via the respiratory tract.
PROLONGATION OF POSTOPERATIVE DISEASE-FREE INTERVAL AND SURVIVAL IN HUMAN COLORECTAL CANCER BY B.C.G. OR B.C.G. PLUS 5-FLUOROURACIL
Authors: GioraM. Mavligit, MichaelA. Burgess, G.Burton Seibert, AndreV. Jubert, CharlesM. Mcbride, EdmundA. Gehan, JordanU. Gutterman, Nayerh Khankhanian, JohnF. Speer, RichardC. Martin, EdwardM. Copeland, EvanM. Hersh
Journal: The Lancet (1976)
Airway structure and inflammatory cells in fatal attacks of asthma
Authors: N Carroll, S Carello, C Cooke, A James
Journal: European Respiratory Journal (1996)

Fatal attacks of asthma usually occur against a background of chronic persistent symptoms, presumably due to chronic airway inflammation and changes in airway wall structure. Death from asthma is usually attributed to excessive airway narrowing due to a combination of muscle spasm and mucous plugging. To test the hypothesis that airway wall structure and/or the inflammatory cell profile are related to the duration of a fatal attack of asthma, inflammatory cell profiles and airway structure were examined in cases of fatal asthma and related to the duration of the fatal attack. In transverse sections of large and small airways from subjects dying from asthma, the numbers of eosinophils, neutrophils and lymphomononuclear cells were counted. The amount of smooth muscle shortening, the areas of airway wall, smooth muscle, mucous gland and cartilage were measured. Cell counts, airway dimensions and muscle shortening were compared in cases dying within 2 h of the fatal attack (short duration) and those dying more than 5 h after the onset of the fatal attack (long duration). In cases with fatal attacks of short duration, the numbers of neutrophils and the mucous gland area were increased and the numbers of eosinophils were reduced compared to cases with fatal attacks of long duration. Lymphocyte numbers, airway wall thickness, the areas of smooth muscle and cartilage and the amount of smooth muscle shortening were similar in the two groups. These findings suggest fatal attacks of asthma may be triggered by an inflammatory stimulus and suggest that increased production of mucous may contribute to sudden death in such cases.
Inverse association between liver fat content and hepatic glucose uptake in patients with type 2 diabetes mellitus
Authors: Ronald Borra, Riikka Lautamäki, Riitta Parkkola, Markku Komu, Paul E. Sijens, Kirsti Hällsten, Jörgen Bergman, Patricia Iozzo, Pirjo Nuutila
Journal: Metabolism (2008)
DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells
Authors: Samia B Bachmann, Sandra C Frommel, Rosalba Camicia, Hans C Winkler, Raffaella Santoro, Paul O Hassa
Journal: Molecular Cancer (2014)

Prostate cancer (PCa) is one of the leading causes of cancer-related mortality and morbidity in the aging male population and represents the most frequently diagnosed malignancy in men around the world. The Deltex (DTX)-3-like E3 ubiquitin ligase (DTX3L), also known as B-lymphoma and BAL-associated protein (BBAP), was originally identified as a binding partner of the diphtheria-toxin-like macrodomain containing ADP-ribosyltransferase-9 (ARTD9), also known as BAL1 and PARP9. We have previously demonstrated that ARTD9 acts as a novel oncogenic survival factor in high-risk, chemo-resistant, diffuse large B cell lymphoma (DLBCL). The mono-ADP-ribosyltransferase ARTD8, also known as PARP14 functions as a STAT6-specific co-regulator of IL4-mediated proliferation and survival in B cells. Co-expression of DTX3L, ARTD8, ARTD9 and STAT1 was analyzed in the metastatic PCa (mPCa) cell lines PC3, DU145, LNCaP and in the normal prostate luminal epithelial cell lines HPE and RWPE1. Effects on cell proliferation, survival and cell migration were determined in PC3, DU145 and/or LNCaP cells depleted of DTX3L, ARTD8, ARTD9, STAT1 and/or IRF1 compared to their proficient control cells, respectively. In further experiments, real-time RT-PCR, Western blot, immunofluorescence and co-immunoprecipitations were conducted to evaluate the physical and functional interactions between DTX3L, ARTD8 and ARTD9. Here we could identify DTX3L, ARTD9 and ARTD8 as novel oncogenic survival factors in mPCa cells. Our studies revealed that DTX3L forms a complex with ARTD8 and mediates together with ARTD8 and ARTD9 proliferation, chemo-resistance and survival of mPCa cells. In addition, DTX3L, ARTD8 and ARTD9 form complexes with each other. Our study provides first evidence that the enzymatic activity of ARTD8 is required for survival of mPCa cells. DTX3L and ARTD9 act together as repressors of the tumor suppressor IRF1 in mPCa cells. Furthermore, the present study shows that DTX3L together with STAT1 and STAT3 is implicated in cell migration of mPCa cells. Our data strongly indicate that a crosstalk between STAT1, DTX3L and ARTD-like mono-ADP-ribosyltransferases mediates proliferation and survival of mPCa cells. The present study further suggests that the combined targeted inhibition of STAT1, ARTD8, ARTD9 and/or DTX3L could increase the efficacy of chemotherapy or radiation treatment in prostate and other high-risk tumor types with an increased STAT1 signaling.
Stimulation of exocrine pancreatic secretion by met-enkephalin.
Authors: L Gullo, P Priori, F Baldoni, G Mattioli
Journal: Gut (1986)

The effect of met-enkephalin on pure exocrine pancreatic secretion was studied in five subjects with external transduodenal drainage of the main pancreatic duct carried out after biliary tract surgery. Intravenous infusion of a low dose of met-enkephalin (0.15 micrograms/kg/h) during submaximal pancreatic stimulation with secretin (25 ng/kg/h) and cerulein (10 ng/kg/h) significantly increased pancreatic outputs. Bicarbonate secretion increased 50% above control values, a more marked effect than the increase in enzyme secretion (maximal rise averaged 22%). The effect of the peptide was rapid, persisted for the duration of met-enkephalin infusion and then tended gradually to diminish.
Detection of Prostate Cancer and Predicting Progression
Authors: James V. Tricoli, Mason Schoenfeldt, Barbara A. Conley
Journal: Clinical Cancer Research (2004)

Carcinoma of the prostate is the second leading cause of male cancer-related death in the United States. Better indicators of prostate cancer presence and progression are needed to avoid unnecessary treatment, predict disease course, and develop more effective therapy. Numerous molecular markers have been described in human serum, urine, seminal fluid, and histological specimens that exhibit varying capacities to detect prostate cancer and predict disease course. However, to date, few of these markers have been adequately validated for clinical use. The purpose of this review is to examine the current status of these markers in prostate cancer and to assess the diagnostic potential for future markers from identified genes and molecules that display loss, mutation, or alteration in expression between tumor and normal prostate tissues. In this review we cite 91 molecular markers that display some level of correlation with prostate cancer presence, disease progression, cancer recurrence, prediction of response to therapy, and/or disease-free survival. We suggest criteria to consider when selecting a marker for further development as a clinical tool and discuss five examples of markers (chromogranin A, glutathione S-transferase pi 1, prostate stem cell antigen, prostate-specific membrane antigen, and telomerase reverse transcriptase) that fulfill some of these criteria. Finally, we discuss how to conduct evaluations of candidate prostate cancer markers and some of the issues involved in the validation process.
Pregnancy and fetal outcomes of symptoms of sleep-disordered breathing
Authors: G. Bourjeily, C.A. Raker, M. Chalhoub, M.A. Miller
Journal: European Respiratory Journal (2010)

The physiological changes of pregnancy may predispose females to develop sleep-disordered breathing (SDB) or protect against it. Studies evaluating outcomes of SDB symptoms in pregnancy are scarce. The goal of this study was to evaluate the prevalence of SDB symptoms in pregnancy and their relationship with pregnancy and neonatal outcomes. A cross-sectional survey of randomly selected immediate postpartum females was performed using the multivariable apnoea prediction index. Record review, including demographics and medical history, was performed. Main outcome measures included pregnancy and neonatal outcomes. 1,000 subjects were recruited. Mean± sd age was 29.1±6.1 yrs. Factors used in the regression analysis included age, body mass index, diabetes, chronic hypertension, multifetal gestations, smoking and renal disease. Snoring was present in 35.1% of subjects. Symptoms of SDB were associated with a higher likelihood of pregnancy-induced hypertension and pre-eclampsia (adjusted OR 2.3, 95% CI 1.4–4.0), gestational diabetes (adjusted OR 2.1, 95% CI 1.3–3.4) and unplanned Caesarean deliveries (adjusted OR 2.1, 95% CI 1.4–3.2) after multivariable regression analysis. Gasping may have been associated with a higher likelihood of preterm delivery, after adjusting for age and multifetal pregnancies (adjusted OR 1.8, 95% CI 1.1–3.2) but this association appeared to be mediated by pre-eclampsia. Symptoms of SDB are common in pregnancy and associated with a higher likelihood of gestational hypertensive disorders, gestational diabetes and unplanned Caesarean deliveries.
Use of a Small Molecule CCR5 Inhibitor in Macaques to Treat Simian Immunodeficiency Virus Infection or Prevent Simian–Human Immunodeficiency Virus Infection
Authors: Ronald S. Veazey, Per Johan Klasse, Thomas J. Ketas, Jacqueline D. Reeves, Michael Piatak, Kevin Kunstman, Shawn E. Kuhmann, Preston A. Marx, Jeffrey D. Lifson, Jason Dufour, Megan Mefford, Ivona Pandrea, Steven M. Wolinsky, Robert W. Doms, Julie A. DeMartino, Salvatore J. Siciliano, Kathy Lyons, Martin S. Springer, John P. Moore
Journal: The Journal of Experimental Medicine (2003)

Human immunodeficiency virus type 1 (HIV-1) fuses with cells after sequential interactions between its envelope glycoproteins, CD4 and a coreceptor, usually CC chemokine receptor 5 (CCR5) or CXC receptor 4 (CXCR4). CMPD 167 is a CCR5-specific small molecule with potent antiviral activity in vitro. We show that CMPD 167 caused a rapid and substantial (4–200-fold) decrease in plasma viremia in six rhesus macaques chronically infected with simian immunodeficiency virus (SIV) strains SIVmac251 or SIVB670, but not in an animal infected with the X4 simian–human immunodeficiency virus (SHIV), SHIV-89.6P. In three of the SIV-infected animals, viremia reduction was sustained. In one, there was a rapid, but partial, rebound and in another, there was a rapid and complete rebound. There was a substantial delay (&amp;gt;21 d) between the end of therapy and the onset of full viremia rebound in two animals. We also evaluated whether vaginal administration of gel-formulated CMPD 167 could prevent vaginal transmission of the R5 virus, SHIV-162P4. Complete protection occurred in only 2 of 11 animals, but early viral replication was significantly less in the 11 CMPD 167-recipients than in 9 controls receiving carrier gel. These findings support the development of small molecule CCR5 inhibitors as antiviral therapies, and possibly as components of a topical microbicide to prevent HIV-1 sexual transmission.
Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism
Authors: Antonius E. van Herwaarden, Els Wagenaar, Cornelia M.M. van der Kruijssen, Robert A.B. van Waterschoot, Johan W. Smit, Ji-Ying Song, Martin A. van der Valk, Olaf van Tellingen, José W.A. van der Hoorn, Hilde Rosing, Jos H. Beijnen, Alfred H. Schinkel
Journal: Journal of Clinical Investigation (2007)

Cytochrome P450 3A (CYP3A) enzymes constitute an important detoxification system that contributes to primary metabolism of more than half of all prescribed medications. To investigate the physiological and pharmacological roles of CYP3A, we generated Cyp3a-knockout (Cyp3a–/–) mice lacking all functional Cyp3a genes. Cyp3a–/– mice were viable, fertile, and without marked physiological abnormalities. However, these mice exhibited severely impaired detoxification capacity when exposed to the chemotherapeutic agent docetaxel, displaying higher exposure levels in response to both oral and intravenous administration. These mice also demonstrated increased sensitivity to docetaxel toxicity, suggesting a primary role for Cyp3a in xenobiotic detoxification. To determine the relative importance of intestinal versus hepatic Cyp3a in first-pass metabolism, we generated transgenic Cyp3a–/– mice expressing human CYP3A4 in either the intestine or the liver. Expression of CYP3A4 in the intestine dramatically decreased absorption of docetaxel into the bloodstream, while hepatic expression aided systemic docetaxel clearance. These results suggest that CYP3A expression determines impairment of drug absorption and efficient systemic clearance in a tissue-specific manner. The genetic models used in this study provide powerful tools to further study CYP3A-mediated xenobiotic metabolism, as well as interactions between CYP3A and other detoxification systems.