tbuckley/cabot-search huggingface dataset:
Oxidative activation of benzidine and its derivatives by peroxidases.
Authors: P D Josephy
Journal: Environmental Health Perspectives (1985)

Benzidine (4,4'-diaminobiphenyl) is a known human carcinogen; exposure to this substance resulted in an epidemic of bladder cancer among workers in the dye industry in Europe and North America. The chemical or enzymatic oxidation of benzidine proceeds via a racial cation detectable by electron spin resonance. Peroxidase-catalyzed oxidation of benzidine generates reactive electrophiles which readily form adducts with phenol and thiol compounds. The structures of these novel metabolites are described. Peroxidases, including prostaglandin synthase, catalyze benzidine binding to protein and nucleic acid; the nature of the resulting adducts is unknown. The relevance of these processes to benzidine carcinogenesis in vivo is the subject of research and debate. A central question remains: is benzidine activated in extra-hepatic target tissues such as bladder epithelium, or transported to these tissues following hepatic oxidative metabolism?
Rate-dependent properties of adenosine-induced negative dromotropism in humans.
Authors: W T Lai, C S Lee, S N Wu
Journal: Circulation (1994)

The antiarrhythmic effects of sodium channel and calcium channel blockers are known to be rate dependent. Little is known about the rate-dependent effect of adenosine on human atrioventricular (AV) nodal conduction. The purpose of this study was to determine whether the negative dromotropic effect of adenosine is dependent on heart rate.Atrial pacing at 20-millisecond increments decreasing stepwise was performed, and the curves that relate the AH interval to the atrial pacing cycle length were analyzed. The change in AV nodal function was evaluated in three protocols: (1) In 8 group 1A and 6 group 1B patients, an intravenous infusion of adenosine at a dose of 140 and 320 micrograms.kg-1.min-1 was given, respectively; (2) a bolus injection of a fixed dose of adenosine was given to 12 group 2A patients without and 6 group 2B patients with propranolol (0.1 mg/kg) treatment; and (3) in 12 group 3 patients, the AV nodal function was evaluated after intravenous propranolol (0.05 mg/kg) and after subsequent intravenous aminophylline (loading dose, 5 mg/kg; maintenance dose, 0.9 mg.kg-1.h-1). No significant depression of AV nodal function could be demonstrated during intravenous infusion of adenosine. The bolus injection of adenosine could prolong the AH interval, which was dependent on heart rate and more significant at a shorter pacing cycle length. Intravenous propranolol significantly depressed the AV nodal conduction and shifted the curves of the AH interval versus the pacing cycle length to the right. Subsequent intravenous aminophylline shortened the AV nodal conduction time, however, in a rate-independent manner.The negative dromotropic effects induced by intravenous bolus injection of adenosine became more pronounced at fast atrial pacing rates. These results indicate that adenosine causes rate-dependent prolongation of AV nodal conduction in humans.
Human immunodeficiency virus (HIV) infection in CD4+ T lymphocytes genetically deficient in LFA-1: LFA-1 is required for HIV-mediated cell fusion but not for viral transmission.
Authors: G Pantaleo, L Butini, C Graziosi, G Poli, S M Schnittman, J J Greenhouse, J I Gallin, A S Fauci
Journal: The Journal of Experimental Medicine (1991)

In the present study, we demonstrated that expression of the LFA-1 molecule is necessary for cell fusion and syncytia formation in human immunodeficiency virus (HIV)-infected CD4+ T lymphocytes. In contrast, the lack of expression of LFA-1 does not influence significantly cell-to-cell transmission of HIV. In fact, LFA-1- T lymphocytes obtained from a leukocyte adhesion deficiency patient were unable to fuse and form syncytia when infected with HIV-1 or HIV-2, despite the fact that efficiency of HIV infection (i.e., virus entry, HIV spreading, and levels of virus replication) was comparable with that observed in LFA-1+ T lymphocytes. In addition, we provide evidence that LFA-1 by mediating cell fusion contributes to the depletion of HIV-infected CD4+ T lymphocytes in vitro.
Adjuvant Paclitaxel and Trastuzumab for Node-Negative, HER2-Positive Breast Cancer
Authors: Sara M. Tolaney, William T. Barry, Chau T. Dang, Denise A. Yardley, Beverly Moy, P. Kelly Marcom, Kathy S. Albain, Hope S. Rugo, Matthew Ellis, Iuliana Shapira, Antonio C. Wolff, Lisa A. Carey, Beth A. Overmoyer, Ann H. Partridge, Hao Guo, Clifford A. Hudis, Ian E. Krop, Harold J. Burstein, Eric P. Winer
Journal: New England Journal of Medicine (2015)

No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)-positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab.We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease.The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contralateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption.Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.).
A prospective open-label pilot study of fluvastatin on proinflammatory and prothrombotic biomarkers in antiphospholipid antibody positive patients
Authors: Doruk Erkan, Rohan Willis, Vijaya L Murthy, Gurjot Basra, JoAnn Vega, Patricia Ruiz-Limón, Ana Laura Carrera, Elizabeth Papalardo, Laura Aline Martínez-Martínez, Emilio B González, Silvia S Pierangeli
Journal: Annals of the Rheumatic Diseases (2013)

To determine if proinflammatory and prothrombotic biomarkers are differentially upregulated in persistently antiphospholipid antibody (aPL)-positive patients, and to examine the effects of fluvastatin on these biomarkers.Four groups of patients (age 18-65) were recruited: (a) primary antiphospholipid syndrome; (b) systemic lupus erythematosus (SLE) with antiphospholipid syndrome (APS) (SLE/APS); (c) persistent aPL positivity without SLE or APS (Primary aPL); and (d) persistent aPL positivity with SLE but no APS (SLE/aPL). The frequency-matched control group, used for baseline data comparison, was identified from a databank of healthy persons. Patients received fluvastatin 40 mg daily for 3 months. At 3 months, patients stopped the study medication and they were followed for another 3 months. Blood samples for 12 proinflammatory and prothrombotic biomarkers were collected monthly for 6 months.Based on the comparison of the baseline samples of 41 aPL-positive patients with 30 healthy controls, 9/12 (75%) biomarkers (interleukin (IL)-6, IL1β, vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)-α, interferon (IFN)-α, inducible protein-10 (IP10), soluble CD40 ligand (sCD40L), soluble tissue factor (sTF) and intracellular cellular adhesion molecule (ICAM)-1) were significantly elevated. Twenty-four patients completed the study; fluvastatin significantly and reversibly reduced the levels of 6/12 (50%) biomarkers (IL1β, VEGF, TNFα, IP10, sCD40L and sTF).Our prospective mechanistic study demonstrates that proinflammatory and prothrombotic biomarkers, which are differentially upregulated in persistently aPL-positive patients, can be reversibly reduced by fluvastatin. Thus, statin-induced modulation of the aPL effects on target cells can be a valuable future approach in the management of aPL-positive patients.
New staging system and a registry for perihilar cholangiocarcinoma
Authors: Michelle L. DeOliveira, Richard D. Schulick, Yuji Nimura, Charles Rosen, Gregory Gores, Peter Neuhaus, Pierre-Alain Clavien
Journal: Hepatology (2011)

Perihilar cholangiocarcinoma is one of the most challenging diseases with poor overall survival. The major problem for anyone trying to convincingly compare studies among centers or over time is the lack of a reliable staging system. The most commonly used system is the Bismuth-Corlette classification of bile duct involvement, which, however, does not include crucial information such as vascular encasement and distant metastases. Other systems are rarely used because they do not provide several key pieces of information guiding therapy. Therefore, we have designed a new system reporting the size of the tumor, the extent of the disease in the biliary system, the involvement of the hepatic artery and portal vein, the involvement of lymph nodes, distant metastases, and the volume of the putative remnant liver after resection. The aim of this system is the standardization of the reporting of perihilar cholangiocarcinoma so that relevant information regarding resectability, indications for liver transplantation, and prognosis can be provided. With this tool, we have created a new registry enabling every center to prospectively enter data on their patients with hilar cholangiocarcinoma (). The availability of such standardized and multicenter data will enable us to identify the critical criteria guiding therapy. (HEPATOLOGY 2011;)
Cocarcinogenic Effects of Islet Hormones and <i>N</i>-Nitrosomorpholine in Hepatocarcinogenesis after Intrahepatic Transplantation of Pancreatic Islets in Streptozotocin-Diabetic Rats
Authors: Frank Dombrowski, Christina Maria Jost, Steffen Manekeller, Matthias Evert
Journal: Cancer Research (2005)

In contrast to high local insulin levels obtained after low-number transplantation (n = 350) of islets of Langerhans into the livers of diabetic rats, low insulin levels after high-number transplantation (n = 1,000) do not suffice to induce hepatocarcinogenesis. Herein, we investigated the possible cocarcinogenic potential of high and, in particular, low insulin levels, combining this in vivo model with a chemical model of hepatocarcinogenesis after administration of N-nitrosomorpholine (NNM). In three main experiments, different schemes of single or continuous NNM administration were combined with different transplantation procedures in diabetic or nondiabetic animals, i.e., low-number and high-number islet transplantation, transplantation of polystyrene particles, and sham transplantation. Animals were sacrificed between 3 and 53 weeks after transplantation procedures. Evidence for the cocarcinogenic effects of NNM and insulin was provided in each main experiment. NNM treatment after low-number islet transplantation resulted in an increase in the number of preneoplastic hepatocellular foci, and a significant increase in the number and an earlier appearance of hepatocellular adenomas and carcinomas compared with controls. Most intriguing was the increase in preneoplastic foci after combined NNM treatment and high-number islet transplantation, proving that insulin, even in lower doses, has at least cocarcinogenic effects on the downstream hepatocytes and thus promotes an otherwise initiated hepatocarcinogenic process. Conclusively, intrahepatic transplantation of pancreatic islets acts as a strong cocarcinogenic factor together with NNM in streptozotocin-diabetic rats.
Expression of a Soluble Complement Inhibitor Protects Transgenic Mice from Antibody-Induced Acute Renal Failure
Authors: BRIGITTE SCHILLER, PATRICK N. CUNNINGHAM, JESSY J. ALEXANDER, LIHUA BAO, V. MICHAEL HOLERS, RICHARD J. QUIGG
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Crry is a potent complement regulator in rodents that inhibits C3 convertases. In rats, intrarenal arterial injection of anti-glomerular endothelial cell (GEN) antibodies leads to complement-dependent microvascular injury and acute renal failure. In this study, a mouse variant of this model and the effects of complement inhibition were examined. Transgenic mice that overexpressed soluble Crry systemically and in their kidneys were studied. Anti-GEN IgG was injected intravenously into eight Crry transgenic mice and seven transgene-negative littermates (which were used as control animals). Thirty h after injection, blood urea nitrogen (BUN) levels were 30.3 ± 4.4 and 114.8 ± 23.5 mg/dl for transgene-positive and -negative animals, respectively ( P = 0.012). Four of five transgene-negative animals with BUN levels of &gt;100 mg/dl were anuric; the remaining animal exhibited minimal albuminuria and no detectable urinary C3. In animals with renal failure, glomerular capillary collapse and tubular necrosis were observed. There was significant tubular staining for C3 in transgene-negative animals, with cellular and basal distributions, both of which were statistically greater than those in transgene-positive animals. Tubular cell C3 staining was strongly correlated with BUN values ( r = 0.83, P &lt; 0.001), as was C9 staining ( r = 0.56, P = 0.037), suggesting that complement activation to the C5b-9 membrane attack complex had a casual role in renal failure. Thus, systemic injection of anti-GEN antibodies into mice leads to acute renal failure, with glomerular and tubular injury. Animals that overexpress soluble Crry in renal tubules and elsewhere are protected from the acute renal failure that occurs in this model, which ultimately seems to develop because of complement activation focused on tubules.
Transcriptional Coactivator with PDZ-binding Motif Is Essential for Normal Alveolarization in Mice
Authors: Akihisa Mitani, Takahide Nagase, Kazunori Fukuchi, Hiroyuki Aburatani, Ryosuke Makita, Hiroki Kurihara
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Transcriptional coactivator with PDZ-binding motif (TAZ) is assumed to act as a coactivator of several transcription factors including smad2/3. In the lung, surfactant protein C (Sftpc) is known to be a downstream target of thyroid transcription factor-1 (TTF-1)-TAZ transcriptional coactivation.The lung phenotype of Taz-deficient mice was explored.Taz-deficient mice were analyzed pathologically and physiologically. Next, we performed microarray analysis to determine the genes closely related to abnormal lung development. Finally, Taz-heterozygous mice were injected with bleomycin.Taz-deficient homozygotes showed abnormal alveolarization during lung development, which caused in adult mice airspace enlargement mimicking emphysema. There was no significant difference in the expression of Sftpc between wild-type and Taz-deficient lungs. Instead, microarray analysis identified some candidate downstream genes related to the pathogenesis, including the connective tissue growth factor (Ctgf) gene, which is required for normal lung development. In vitro studies showed that TAZ up-regulated Ctgf expression not only by reinforcing transforming growth factor-beta/smad signals, but also by interfering in the more proximal Ctgf promoter region (from bp -123 to -76), defined as the TAZ response element. Furthermore, Taz-heterozygous mice were resistant to bleomycin-induced lung fibrosis.The results indicate the importance of TAZ in lung alveolarization and its involvement in the pathogenesis of lung fibrosis.
Red cell NADP+ and NADPH in glucose-6-phosphate dehydrogenase deficiency.
Authors: H N Kirkman, G D Gaetani, E H Clemons, C Mareni
Journal: Journal of Clinical Investigation (1975)

Extraction in the presence of sodium hydroxide and cysteine allows estimates of NADPH and total NADP in human red cells without the erroneously high values of NADP+ obtained with earlier methods. An application of this technique to G6PD-deficient cells reveals that most of the nucleotide is in the oxidized form. In contrast, normal red cells have nearly all of the nucleotide in the reudced form. In addition to providing information concerning the intracellular regulation of the hexose monophosphate shunt, these findings support the concept that G6PD deficiency is a product-deficiency disorder.
Involvement of the K and I regions of the H-2 complex in resistance to hemopoietic allografts.
Authors: G Drizlikh, J Schmidt-Sole, B Yankelevich
Journal: The Journal of Experimental Medicine (1984)

Irradiated (H-2b X H-2k)F1 and (H-2b X H-2d)F1 recipients strongly resist the growth of H-2b parental bone marrow cells and do not resist marrow grafts from non-H-2b parents such as C3H and BALB/c. This phenomenon of hybrid resistance has been shown to be under genetic control of the H-2D-linked loci and was interpreted by Cudkowicz (9) as due to the existence of H-2D-linked recessive hemopoietic histocompatibility genes. To check whether the H-2D-linked loci are solely responsible for the fate of bone marrow allografts, we measured the strength of resistance of irradiated (B6 X C3H)F1 and (B6 X BALB/c)F1 recipients toward bone marrow grafts from a set of H-2 recombinant and F1 hybrid donors carrying either the H-2b, H-2d, and H-2k alleles. We found that growth of all H-2b grafts was resisted, although to different degrees. Resistance was minimal when donors shared with the input strain of a corresponding F1 hybrid the H-2K and H-2I regions, or when both F1 donors and F1 recipients formed identical unique hybrid Ia molecules. In addition, H-2b grafts were resisted by congenic, H-2D-identical, H-2K-and H-2I-incompatible recipients. The fate of grafts from H-2Dd donors seemed to depend on the incompatibility of the combinatorial determinant Ia.22. If both donor and recipient expressed such a determinant (either in the cis or in the transposition), or if neither could form such a determinant, grafts were not resisted. The H-2Dk allele is not the main or only factor that confers on the C3H parental bone marrow cells the ability to grow unresisted in (B6 X C3H)F1 recipients. Grafts from congenic C3H.OH donors, carrying the same H-2Dk alleles and differing in the left part of the H-2 complex, were resisted by the F1 recipients. We conclude that both class I (K and D) and class II (I-A and I-E) major histocompatibility complex genes, rather than hypothetical hemopoietic histocompatibility genes control hemopoietic resistance. To reconcile codominant inheritance of classic H-2 antigens with the apparent recessive inheritance of hybrid resistance, we assume that there exist parental determinants that are not formed in some F1 hybrids due to preferential association of either Ia alpha chains with allogeneic beta chains or of class I antigens with allogeneic or hybrid class II restriction elements.
A Placebo-Controlled, Double-Blind Study of the Efficacy and Safety of Aripiprazole in Patients With Acute Bipolar Mania
Authors: Paul E. Keck, Ronald Marcus, Stavros Tourkodimitris, Mirza Ali, Amy Liebeskind, Anutosh Saha, Gary Ingenito
Journal: American Journal of Psychiatry (2003)

The authors compared the efficacy and safety of aripiprazole, a novel antipsychotic, to placebo for treatment of patients in an acute manic or mixed episode of bipolar disorder.This 3-week, multicenter, double-blind study randomly assigned 262 bipolar disorder patients in an acute manic or mixed episode to aripiprazole, 30 mg/day (reduced to 15 mg/day if needed for tolerability), or placebo. Patients remained hospitalized for at least 2 of the weeks. The primary efficacy measure was mean change from baseline in total score on the Young Mania Rating Scale; response was defined as a decrease in score of > or =50%.Aripiprazole produced statistically significant mean improvements in total score on the Young Mania Rating Scale compared with placebo (-8.2 versus -3.4, respectively) and produced a significantly higher response rate (40% versus 19%). For key efficacy variables (response per Young Mania Rating Scale; Clinical Global Impression-Bipolar Version scores for severity of illness [mania] and change from preceding phase [mania]), aripiprazole separated from placebo by day 4. The completion rate was significantly higher with aripiprazole than with placebo (42% versus 21%). Discontinuations due to adverse events did not differ significantly between the aripiprazole and placebo groups. There were no significant changes in body weight versus placebo, and aripiprazole was not associated with elevated serum prolactin or QTc prolongation.Aripiprazole had significantly greater efficacy than placebo for the treatment of bipolar disorder patients in acute manic or mixed episodes and was safe and well tolerated in this randomized controlled trial.
Expression Profile–Defined Classification of Lung Adenocarcinoma Shows Close Relationship With Underlying Major Genetic Changes and Clinicopathologic Behaviors
Authors: Toshiyuki Takeuchi, Shuta Tomida, Yasushi Yatabe, Takayuki Kosaka, Hirotaka Osada, Kiyoshi Yanagisawa, Tetsuya Mitsudomi, Takashi Takahashi
Journal: Journal of Clinical Oncology (2006)

Purpose This study was conducted to gain insight into the relationship between expression profiles and underlying genetic changes, which are known to be important for the pathogenesis of lung cancers. Methods Expression profiles of 18,175 unique genes and three major targets for genetic changes, p53, epidermal growth factor receptor (EGFR), and K-ras, were investigated in 149 patients with non–small-cell lung cancer, including 90 patients with adenocarcinoma to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms. Results This study successfully established a basis for expression profile-defined classification, which can classify adenocarcinomas into two major types, terminal respiratory unit (TRU) type and non–TRU type. Our GO term–based identifier of particular biologic processes, molecular functions, and cellular compartments clearly showed characteristic retention of normal peripheral lung features in TRU type, in sharp contrast to the significant association of non–TRU type with cell cycling and proliferation-related features. While significantly higher frequency of EGFR mutation was observed in TRU type, we found that the presence of EGFR mutations was a significant predictor of shorter postoperative survival for TRU type, independent of disease stage. We were also able to identify a set of genes in vivo with significant upregulation in the presence of EGFR mutations. Conclusion This study has shed light on heterogeneity in lung cancers, especially in adenocarcinomas, by establishing a molecularly, genetically, and clinically relevant, expression profile-defined classification. Future studies using independent patient cohorts are warranted to confirm the prognostic significance of EGFR mutations in TRU-type adenocarcinoma.