tbuckley/cabot-search huggingface dataset:
Basal core promoters control the equilibrium between negative cofactor 2 and preinitiation complexes in human cells
Authors: Thomas K Albert, Korbinian Grote, Stefan Boeing, Michael Meisterernst
Journal: Genome biology (2010)

Abstract Background The general transcription factor TFIIB and its antagonist negative cofactor 2 (NC2) are hallmarks of RNA polymerase II (RNAPII) transcription. Both factors bind TATA box-binding protein (TBP) at promoters in a mutually exclusive manner. Dissociation of NC2 is thought to be followed by TFIIB association and subsequent preinitiation complex formation. TFIIB dissociates upon RNAPII promoter clearance, thereby providing a specific measure for steady-state preinitiation complex levels. As yet, genome-scale promoter mapping of human TFIIB has not been reported. It thus remains elusive how human core promoters contribute to preinitiation complex formation in vivo . Results We compare target genes of TFIIB and NC2 in human B cells and analyze associated core promoter architectures. TFIIB occupancy is positively correlated with gene expression, with the vast majority of promoters being GC-rich and lacking defined core promoter elements. TATA elements, but not the previously in vitro defined TFIIB recognition elements, are enriched in some 4 to 5% of the genes. NC2 binds to a highly related target gene set. Nonetheless, subpopulations show strong variations in factor ratios: whereas high TFIIB/NC2 ratios select for promoters with focused start sites and conserved core elements, high NC2/TFIIB ratios correlate to multiple start-site promoters lacking defined core elements. Conclusions TFIIB and NC2 are global players that occupy active genes. Preinitiation complex formation is independent of core elements at the majority of genes. TATA and TATA-like elements dictate TFIIB occupancy at a subset of genes. Biochemical data support a model in which preinitiation complex but not TBP-NC2 complex formation is regulated.
Association between Chlamydia pneumoniae antibodies and wheezing in young children and the influence of sex
Authors: E Normann, J Gnarpe, B Wettergren, C Janson, M Wickman, L Nordvall
Journal: Thorax (2006)

<b>Background:</b> The proposed association between <i>Chlamydia pneumoniae</i> (Cpn) infection and wheezing needs further clarification. <b>Methods:</b> Serum samples obtained from 1581 children aged 4 years in a population based cohort were tested for antibodies to Cpn and IgE antibodies to common allergens. Data on environmental factors and disease were collected prospectively from birth. <b>Results:</b> The occurrence of IgG antibodies to Cpn at 4 years of age was associated with reported wheezing at different ages; however, these findings were most often not significant. In girls, the occurrence of anti-Cpn IgG was associated with wheezing at the ages of 1, 2, and 4 years (odds ratios (ORs) 3.41 (95% confidence interval (CI) 1.46 to 7.96), 2.13 (95% CI 1.02 to 4.44), and 2.01 (95% CI 1.14 to 3.54), respectively), and even higher ORs were observed for each age category when only high level antibody responses to Cpn were analysed. At the time of blood sampling the association between anti-Cpn IgG and wheezing was restricted to girls without atopic sensitisation (OR 2.39 (95% CI 1.25 to 4.57). No associations with wheezing were detected in boys, in whom IgE sensitisation was inversely associated with the presence of anti-Cpn IgG (OR 0.49 (95% CI 0.26 to 0.90). <b>Conclusions:</b> This study suggests an association between evidence of earlier Cpn infection and a history of wheezing in young girls. Infection with Cpn may be an important risk factor for wheezing and possibly for non-atopic asthma, predominantly in girls.
HIV-1 Genotypic Resistance Patterns Predict Response to saquinavir–ritonavir Therapy in Patients in Whom Previous Protease Inhibitor Therapy Had Failed
Authors: Andrew R. Zolopa, Robert W. Shafer, Ann Warford, Jose G. Montoya, Phillip Hsu, David Katzenstein, Thomas C. Merigan, Brad Efron
Journal: Annals of Internal Medicine (1999)

Background: Tests for resistance to HIV drugs are available for clinical use; however, their predictive value has not been fully assessed. Objectives: To determine HIV-1 genotypic predictors of a virologic response to saquinavir–ritonavir therapy in patients in whom at least one previous protease inhibitor-containing regimen had failed and to compare the predictive value of baseline genotype with that of standard clinical evaluation. Design: Retrospective clinical cohort study. Setting: University-based HIV clinic. Patients: 54 HIV-1-infected adults treated with saquinavir–ritonavir who had experienced virologic failure while receiving a protease inhibitor-containing regimen for at least 3 months. Measurements: HIV-1 reverse transcriptase and protease gene sequences, CD4 cell counts, clinical characteristics, detailed antiretroviral treatment history, and plasma HIV-1 RNA levels at baseline and at three follow-up time points (median, 4, 12, and 26 weeks). Virologic failure was defined as a plasma HIV RNA level greater than 1000 copies/mL. Results: In 22 patients (41%), a plasma HIV-1 RNA level less than 500 copies/mL was achieved by week 12; in 15 patients (28%), this response was maintained through week 26. Clinical characteristics predicting a poorer response included a diagnosis of AIDS, lower CD4 cell count, and higher plasma HIV RNA level (P < 0.03). Number of previous nucleoside reverse transcriptase inhibitors, previous protease inhibitor therapy, and duration of previous protease inhibitor therapy were predictors of poorer response (P < 0.01). Multivariate regression models revealed that protease mutations present at the initiation of saquinavir–ritonavir therapy were the strongest predictors of virologic response. A model of clinical features explained up to 45% of the variation in virologic outcomes by week 12, whereas the explained variance was 71% when genotypic predictors were included. Conclusions: In patients in whom protease inhibitor-containing antiretroviral therapy fails, HIV-1 genotype is predictive of virologic response to subsequent therapy. This predictive capacity adds to that of standard clinical evaluation.
Type 2 diabetes prevention programme is needed to tackle projected five million rise in cases
Authors: Adrian O’Dowd
Journal: BMJ (2015)

A nationwide diabetes prevention programme, due to start next year, is needed to help prevent an estimated five million people in England who are at risk of type 2 diabetes from developing the disease, Public Health England (PHE) has said.

This conclusion came from a report published on 26 August by PHE,1 which provided what it called the “most accurate and robust estimate” yet of how many people aged over 16 years in England had blood sugar levels in a range showing hyperglycaemia, or a high risk of developing type 2 diabetes.

The report, compiled by PHE’s National Cardiovascular Health Intelligence Network, was commissioned by the NHS Diabetes Prevention Programme, which will support people in reducing their …
Effect of BCG on Alloimmune Cell-Mediated Cytotoxicity in (C57BL/6J ♀ × A/J ♂)F1 Mice. II. Correlation With BCG Activity in Syngeneic Tumor Systems2
Authors: Martin Davies, Edris Sabbadini
Journal: JNCI Journal of the National Cancer Institute (1978)

The effectiveness of selected BCG regimens to produce an activation of cell-mediated cytotoxicity (CMC) in an allogeneic tumor system was compared with its ability to cause tumor regression in syngeneic tumor systems. In the tumor system selected In both Inbred LEW rats and inbred C57BL/6J and (C57BL/6J♀ × A/J♂)F1 mice, a correlation was observed in that BCG treatments that caused marked CMC activation in the allogeneic tumor systems also effectively caused tumor regression and increased animal survival in syngeneic systems. It was concluded that the allogeneic CMC reaction can be used to predict the capacity of BCG to cause tumor rejection.
Intravenous albumin infusion is an effective therapy for hyponatraemia in cirrhotic patients with ascites.
Authors: P A McCormick, P Mistry, G Kaye, A K Burroughs, N McIntyre
Journal: Gut (1990)

The treatment of moderate to severe hyponatraemia in patients with decompensated liver disease is unsatisfactory. We report our preliminary experience using intravenous infusion of albumin to treat this condition. Three patients with cirrhosis, ascites, and hyponatraemia responded satisfactorily to treatment; one patient with fulminant hepatitis B did not respond. Intravenous albumin infusion is a safe and effective therapy for patients with cirrhosis complicated by hyponatraemia. Its main role may be in preparing patients for surgery, particularly liver transplantation.
Phase I Study of Depsipeptide in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Report
Authors: Maryam Fouladi, Wayne L. Furman, Thomas Chin, Burgess B. Freeman, Lorina Dudkin, Clinton F. Stewart, Mark D. Krailo, Roseanne Speights, Ashish M. Ingle, Peter J. Houghton, John Wright, Peter C. Adamson, Susan M. Blaney
Journal: Journal of Clinical Oncology (2006)

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with refractory or recurrent solid tumors.Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques.There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m(2) with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed.Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.
A Prospective Study of the Immune System Activation Biomarker Neopterin and Colorectal Cancer Risk
Authors: Krasimira Aleksandrova, Shu-Chun Chuang, Heiner Boeing, Hui Zuo, Grethe S Tell, Tobias Pischon, Mazda Jenab, Bas Bueno-de-Mesquita, Stein Emil Vollset, Øivind Midttun, Per Magne Ueland, Veronika Fedirko, Mattias Johansson, Elisabete Weiderpass, Gianluca Severi, Antoine Racine, Marie-Christine Boutron-Ruault, Rudolf Kaaks, Tilman Kühn, Anne Tjønneland, Kim Overvad, J Ramón Quirós, Paula Jakszyn, María-José Sánchez, Miren Dorronsoro, Maria-Dolores Chirlaque, Eva Ardanaz, Kay-Tee Khaw, Nicholas J Wareham, Ruth C Travis, Antonia Trichopoulou, Pagona Lagiou, Dimitrios Trichopoulos, Domenico Palli, Sabina Sieri, Rosario Tumino, Salvatore Panico, Anne M May, Richard Palmqvist, Ingrid Ljuslinder, So Yeon J Kong, Heinz Freisling, Marc J Gunter, Yunxia Lu, Amanda J Cross, Elio Riboli, Paolo Vineis
Journal: JNCI Journal of the National Cancer Institute (2015)

Neopterin may be relevant for colorectal cancer (CRC) development, as a biomarker of cellular immune activity exerting pleiotropic effects on cellular ageing, oxidative stress, and inflammation. So far, the association between prediagnostic neopterin and colon and rectal cancer risk has not been evaluated in human populations. A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort using data on plasma concentrations of total neopterin (T-N, sum of neopterin and 7,8-dihydroneopterin) in 830 incident CRC case patients (561 colon and 269 rectal) matched within risk sets to 830 control participants. A subsequent replication study used data from the Hordaland Health Study, where 173 CRC case patients have been diagnosed among 6594 healthy participants over 12 years of follow-up. After multivariable adjustment for a priori chosen CRC risk factors, a "U-shaped" association of T-N with CRC was revealed. Compared with the second quintile of the T-N distribution, the relative risks for the first, third, fourth, and fifth quintiles were 2.37 (95% CI = 1.66 to 3.39), 1.24 (95% CI = 0.87 to 1.77), 1.55 (95% CI = 1.08 to 2.22), and 2.31 (95% CI = 1.63 to 3.27), respectively. Replication of these associations within the Hordaland Health Study yielded similar results. No differences have been observed when the associations were explored by colon and rectal cancer site (two-sided Pdifference = .87) and after excluding case patients diagnosed within the first four follow-up years. These novel findings provide evidence of the role of both suppressed and activated cell-mediated immunity as reflected by prediagnostic T-N concentrations in the development of CRC.
Treatment of Patients Over 64 Years of Age With Type 2 Diabetes
Authors: Stefano Del Prato, Robert J. Heine, Leonard Keilson, Christiane Guitard, Sharon G. Shen, Rebecca P. Emmons
Journal: Diabetes Care (2003)

To evaluate the impact of renal impairment (RI) (estimated creatinine clearance [Cl(cr)] <60 ml/min per 1.73 m(2)) and low baseline HbA(1c) (<7.5%) on comorbidity in patients with type 2 diabetes, and to assess the efficacy and safety of nateglinide monotherapy in these patients and in subgroups of patients over age 64 years (elderly) and elderly with RI.Retrospective subgroup analyses were performed on pooled data from all completed nateglinide studies (12 randomized, double blind trials and 1 open trial) in patients with type 2 diabetes. A total of 3,702 patients with > or =1 postbaseline safety evaluation received monotherapy with nateglinide (n = 2,204), metformin (n = 436), glyburide (n = 293), or placebo (n = 769). Efficacy (HbA(1c)) was evaluated in pooled data from four studies with similar design using 120 mg nateglinide (n = 544) versus placebo (n = 521). Evaluations were performed in the overall population and subgroups of patients over age 64 years. Specific considerations were given to RI, comorbidity, and baseline HbA(1c).Patients over age 64 years (n = 1,170) represented 31.6% of the study population. Undiagnosed RI was common in the elderly with 83.4% of all patients being in this subgroup. Patients over 64 years with RI had a higher prevalence of cardio- and microvascular comorbidity compared with the overall population and all patients over age 64 years. Statistically significant HbA(1c) reductions versus placebo were observed with nateglinide in patients over age 64 years and elderly with RI patients at study end point (-0.9% and -1.1% in each subgroup, P < 0.01). Nateglinide was well tolerated with a low incidence of hypoglycemia in all subgroups, including those with RI and low baseline HbA(1c).RI and comorbidity are common in patients over age 64 years with type 2 diabetes. Nateglinide was effective and well tolerated in all treated patients. In subgroups in which metformin and long-acting sulfonylureas must be used with caution, nateglinide had a low risk of adverse events and hypoglycemia.
Neamine Inhibits Xenografic Human Tumor Growth and Angiogenesis in Athymic Mice
Authors: Saori Hirukawa, Karen A. Olson, Takanori Tsuji, Guo-fu Hu
Journal: Clinical Cancer Research (2005)

We have previously shown that the aminoglycoside antibiotic neomycin blocks the nuclear translocation of angiogenin and inhibits its angiogenic activity. However, neomycin has not been considered as a favorable drug candidate for clinical development because of its known nephrotoxicity and ototoxicity. The aim of this study is to determine whether neamine, a nontoxic derivative of neomycin, possesses antitumor activity.The effect of neamine on the nuclear translocation of angiogenin was examined by means of immunofluorescence and Western blotting. The antitumor activity of neamine was determined with three different animal models.Neamine effectively blocked the nuclear translocation of angiogenin in endothelial cells and inhibited angiogenin-induced cell proliferation. It inhibited the establishment of human tumor xenografts in athymic mice in both ectopic and orthotopic tumor models. It also inhibited the progression of established human tumor transplants, whereas the structurally related antibiotic paromomycin had no effect. Immunohistochemical staining showed that both angiogenesis and cancer cell proliferation are inhibited by neamine.These results suggest that the nontoxic aminoglycoside antibiotic neamine is an effective inhibitor of nuclear translocation of angiogenin and may serve as an inhibitor for angiogenin-induced angiogenesis and cancer progression.
Adaptation to organic dust exposure: a potential role of l-selectin shedding?
Authors: E. Israël-Assayag, Y. Cormier
Journal: European Respiratory Journal (2002)

Swine confinement workers, exposed to high levels of organic dust, present a high prevalence of respiratory symptoms but show only mild lung inflammation. This contrasts with the intense inflammatory response observed when naive subjects are exposed to the same environment. Shedding of l-selectin may regulate the recruitment of inflammatory cells and explain this discrepancy. Soluble l-selectin (sl-selectin) levels were measured in sera of 36 workers, 35 control subjects and eight healthy volunteers briefly and repeatedly exposed to swine confinement buildings. White blood cell counts (WBC) and serum interleukin (IL)-6 levels were measured as markers of systemic inflammation. Higher concentrations of sl-selectin were found in the sera of workers than in controls (1452±62 ng·mL −1 and 872±25 ng·mL −1 , respectively) whereas no differences were detected before and after acute repeated exposures of exposed volunteers. WBC were increased after exposure in exposed volunteers but not in workers. Both workers and exposed volunteers had increased IL-6 serum levels, although it was more pronounced for the exposed volunteers. These results support the hypothesis that shedding of l-selectin may downregulate the inflammatory response to organic dust-contaminated environments and constitute one mechanism of adaptation to the farm environment.
MYH9 is associated with nondiabetic end-stage renal disease in African Americans
Authors: W H Linda Kao, Michael J Klag, Lucy A Meoni, David Reich, Yvette Berthier-Schaad, Man Li, Josef Coresh, Nick Patterson, Arti Tandon, Neil R Powe, Nancy E Fink, John H Sadler, Matthew R Weir, Hanna E Abboud, Sharon G Adler, Jasmin Divers, Sudha K Iyengar, Barry I Freedman, Paul L Kimmel, William C Knowler, Orly F Kohn, Kristopher Kramp, David J Leehey, Susanne B Nicholas, Madeleine V Pahl, Jeffrey R Schelling, John R Sedor, Denyse Thornley-Brown, Cheryl A Winkler, Michael W Smith, Rulan S Parekh
Journal: Nature Genetics (2008)
Randomized Phase II Trial of the Clinical and Biological Effects of Two Dose Levels of Gefitinib in Patients With Recurrent Colorectal Adenocarcinoma
Authors: Mace L. Rothenberg, Bonnie LaFleur, Donna E. Levy, Mary Kay Washington, Sherry L. Morgan-Meadows, Ramesh K. Ramanathan, Jordan D. Berlin, Al B. Benson, Robert J. Coffey
Journal: Journal of Clinical Oncology (2005)

The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha).One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome.Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance.Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.
MEK and the inhibitors: from bench to bedside
Authors: Akintunde Akinleye, Muhammad Furqan, Nikhil Mukhi, Pavan Ravella, Delong Liu
Journal: Journal of Hematology & Oncology (2013)

Abstract Four distinct MAP kinase signaling pathways involving 7 MEK enzymes have been identified. MEK1 and MEK2 are the prototype members of MEK family proteins. Several MEK inhibitors are in clinical trials. Trametinib is being evaluated by FDA for the treatment of metastatic melanoma with BRAF V600 mutation. Selumetinib has been studied in combination with docetaxel in phase II randomized trial in previously treated patients with advanced lung cancer. Selumetinib group had better response rate and progression-free survival. This review also summarized new MEK inhibitors in clinical development, including pimasertib, refametinib, PD-0325901, TAK733, MEK162 (ARRY 438162), RO5126766, WX-554, RO4987655 (CH4987655), GDC-0973 (XL518), and AZD8330.