tbuckley/cabot-search huggingface dataset:
Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways
Authors: J. Cortijo, M. Mata, J. Milara, E. Donet, A. Gavaldà, M. Miralpeix, E.J. Morcillo
Journal: European Respiratory Journal (2010)

Mucus hypersecretion and mucin MUC5AC overexpression are pathological features of chronic obstructive pulmonary disease (COPD). This study examines the inhibitory effect of aclidinium, a new long-acting muscarinic antagonist, on MUC5AC expression in human airway epithelial cells. MUC5AC mRNA (RT-PCR) and protein expression (ELISA and immunohistochemistry) were studied in human bronchial tissue and differentiated human airway epithelial cells activated with carbachol (100 μM) or cigarette smoke extract in the absence or presence of aclidinium. Carbachol increased MUC5AC mRNA and protein expression in human bronchus and cultured epithelial cells. Aclidinium inhibited the carbachol-induced MUC5AC mRNA and protein expression with potency (half maximal inhibitory concentration) ∼1 nM in human bronchus and cultured airway epithelial cells. AG1478, a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, inhibited carbachol-induced MUC5AC responses, indicating EGFR transactivation. Aclidinium inhibited carbachol-induced phospho-EGFR and phospho-p44/42 MAPK expression. In cultured airway epithelial cells transfected with small interfering (si)RNA against muscarinic receptor subtypes, siRNA-M3 but not siRNA-M2 blocked carbachol-induced MUC5AC expression. Cigarette smoke-induced MUC5AC upregulation in cultured airway epithelial cells was suppressed by aclidinium. In conclusion, aclidinium decreases carbachol and tobacco smoke-induced MUC5AC overexpression in human airway epithelial cells. This effect may contribute to the clinical efficacy of aclidinium in mucus hypersecretory diseases including COPD.
Demonstration of an antibody-mediated tolerance state and its effect on antibody affinity.
Authors: G Birnbaum, M E Weksler, G W Siskind
Journal: The Journal of Experimental Medicine (1975)

We have described a model of immunological tolerance induced, in adult mice, by a single injection of a moderate dose of a hapten-protein conjugate. The data suggest that the mechanism of this tolerance state is the production of small amounts of high affinity antibody in response to the tolerance-inducing antigen injection. This antibody acts to inhibit the response to a subsequent challenge with antigen in complete Freund's adjuvant by a mechanism comparable to that of passive antibody-medicated immune suppression. It was shown that a small but high affinity. Tolerance was not terminated by transfer of normal syngeneic spleen or peritoneal cells into tolerant animals. Spleen cells from tolerant mice, when transferred into lethally irradiated, syngeneic animals, produced a PFC response which is greater in magnitude and tolerance state had a significant degree of carrier specificity which was shown to be comparable to the carrier specificity of antibody-mediated immune suppression. hus, evidence was presented to show that one mechanism of tolerance in adult animals in the suppressive effect of small amounts of high affinity antibody formed in response to the tolerizing injection of antigen.
Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: Short-term and long-term outcomes
Authors: Liang Peng, Dong-ying Xie, Bing-Liang Lin, Jing Liu, Hai-peng Zhu, Chan Xie, Yu-bao Zheng, Zhi-liang Gao
Journal: Hepatology (2011)

Our study aimed to investigate the short-term efficacy and long-term prognosis of liver failure patients caused by hepatitis B after a single transplantation with autologous marrow mesenchymal stem cells (MMSCs). A total of 527 inpatients with liver failure caused by hepatitis B were recruited and received the same medical treatments, among whom 53 patients underwent a single transplantation with autologous MMSCs. A total of 105 patients matched for age, sex, and biochemical indexes, including alanine aminotransferase (ALT), albumin, total bilirubin (TBIL), prothrombin time (PT), and Model for End-Stage Liver Disease (MELD), comprised the control group. A total of 120 mL of bone marrow was obtained from each patient and then diluted and separated. Then, the MMSC suspension was slowly transfused into the liver through the proper hepatic artery. The success rate of transplantation was 100%, without serious side effects or complications. Levels of ALB, TBIL, and PT and MELD score of patients in the transplantation group were markedly improved from 2-3 weeks after transplantation, compared with those in the control group. At 192 weeks of follow-up, there were no dramatic differences in incidence of hepatocellular carcinoma (HCC) or mortality between the two groups. Additionally, there were no significant differences in the incidence of HCC or mortality between patients with and without cirrhosis in the transplantation group.Autologous MMSC transplantation is safe for liver failure patients caused by chronic hepatitis B. Short-term efficacy was favorable, but long-term outcomes were not markedly improved. In respect to several parameters, this method is preferable for patients with liver cirrhosis and may have potential for reducing their incidence of HCC and mortality.
Very Low Affinity B Cells Form Germinal Centers, Become Memory B Cells, and Participate in Secondary Immune Responses When Higher Affinity Competition Is Reduced
Authors: Joseph M. Dal Porto, Ann M. Haberman, Garnett Kelsoe, Mark J. Shlomchik
Journal: The Journal of Experimental Medicine (2002)

To understand the relationship between the affinity of the B cell antigen receptor (BCR) and the immune response to antigen, two lines of immunoglobulin H chain transgenic (Tg) mice were created. H50Gμa and T1(V23)μa mice express μ H chain transgenes that associate with the λ1 L chains to bind the (4-hydroxy-3-nitrophenyl)acetyl hapten with association constants (Kas) of only 1.2 × 105 M−1 and 3 × 104 M−1, respectively. Both lines mounted substantial antibody-forming cell (AFC) and germinal center (GC) responses. H50Gμa Tg mice also generated memory B cells. T1(V23)μa B cells formed AFC and GCs, but were largely replaced in late GCs by antigen-specific cells that express endogenous BCRs. Thus, B lymphocytes carrying BCRs with affinities previously thought to be irrelevant in specific immune responses are in fact capable of complete T cell–dependent immune responses when relieved of substantial competition from other B cells. The failure to observe such B cells normally in late primary responses and in memory B cell populations is the result of competition, rather than an intrinsic inability of low affinity B cells.
Statin-Induced Diabetes: Will It Change Clinical Practice?
Authors: L. Maria Belalcazar, Vasudevan A. Raghavan, Christie M. Ballantyne
Journal: Diabetes Care (2009)

An increase in the incidence of physician-diagnosed diabetes with rosuvastatin in Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) published recently revived clinical interest in the effects of statins on glycemic control. The study showed that, after almost 2 years of follow-up in men and women with elevated levels of high-sensitivity C-reactive protein but average LDL cholesterol, rosuvastatin therapy was associated with a mild but significant increase in the identification of new-onset diabetes (3% in the statin arm, 2.4% in the placebo arm; P < 0.01) (1). The potential association between statin use and new-onset diabetes gained attention in 2001 when a post hoc analysis of another primary prevention statin trial, the West of Scotland Coronary Prevention Study (WOSCOPS), reported that treatment with pravastatin decreased the hazard of developing type 2 diabetes by 30% (hazard ratio 0.7 [95% CI 0.5–0.99]; P = 0.042) (2). These seemingly contradictory findings flank results from four other statin trials that failed to uncover a significant relationship between statin use and incident type 2 diabetes when the latter was evaluated as a tertiary end point (3–6).

In this issue of Diabetes Care , Rajpathak et al. (7) bring together six randomized placebo-controlled trials to explore diabetes risk with statins using a meta-analytical approach. The authors found that, if they included all six studies in the analysis (a total of 2,082 cases of incident diabetes in 57,593 study participants), there was no significant association between statin use and the development of type 2 diabetes (relative risk 1.06 [95% CI 0.93–1.25]). On the other hand, …
Co-inhibition of NF-κB and JNK is synergistic in TNF-expressing human AML
Authors: Andrew Volk, Jing Li, Junping Xin, Dewen You, Jun Zhang, Xinli Liu, Yechen Xiao, Peter Breslin, Zejuan Li, Wei Wei, Rachel Schmidt, Xingyu Li, Zhou Zhang, Paul C. Kuo, Sucha Nand, Jianke Zhang, Jianjun Chen, Jiwang Zhang
Journal: The Journal of Experimental Medicine (2014)

Leukemic stem cells (LSCs) isolated from acute myeloid leukemia (AML) patients are more sensitive to nuclear factor κB (NF-κB) inhibition-induced cell death when compared with hematopoietic stem and progenitor cells (HSPCs) in in vitro culture. However, inadequate anti-leukemic activity of NF-κB inhibition in vivo suggests the presence of additional survival/proliferative signals that can compensate for NF-κB inhibition. AML subtypes M3, M4, and M5 cells produce endogenous tumor necrosis factor α (TNF). Although stimulating HSPC with TNF promotes necroptosis and apoptosis, similar treatment with AML cells (leukemic cells, LCs) results in an increase in survival and proliferation. We determined that TNF stimulation drives the JNK–AP1 pathway in a manner parallel to NF-κB, leading to the up-regulation of anti-apoptotic genes in LC. We found that we can significantly sensitize LC to NF-κB inhibitor treatment by blocking the TNF–JNK–AP1 signaling pathway. Our data suggest that co-inhibition of both TNF–JNK–AP1 and NF-κB signals may provide a more comprehensive treatment paradigm for AML patients with TNF-expressing LC.
Phase II Study of Lutetium-177–Labeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Metastatic Castration-Resistant Prostate Cancer
Authors: Scott T. Tagawa, Matthew I. Milowsky, Michael Morris, Shankar Vallabhajosula, Paul Christos, Naveed H. Akhtar, Joseph Osborne, Stanley J. Goldsmith, Steve Larson, Neeta Pandit Taskar, Howard I. Scher, Neil H. Bander, David M. Nanus
Journal: Clinical Cancer Research (2013)

Abstract Purpose: To assess the efficacy of a single infusion of radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (lutetium-177; 177Lu) by prostate-specific antigen (PSA) decline, measurable disease response, and survival. Experimental Design: In this dual-center phase II study, two cohorts with progressive metastatic castration-resistant prostate cancer received one dose of 177Lu-J591 (15 patients at 65 mCi/m2, 17 at 70 mCi/m2) with radionuclide imaging. Expansion cohort (n = 15) received 70 mCi/m2 to verify response rate and examine biomarkers. Results: Forty-seven patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received 177Lu-J591. A total of 10.6% experienced ≥50% decline in PSA, 36.2% experienced ≥30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity, with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. A total of 25.5% experienced grade 4 neutropenia, with one episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m2) resulted in more 30% PSA declines (46.9% vs. 13.3%, P = 0.048) and longer survival (21.8 vs. 11.9 months, P = 0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious nonhematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond. Conclusion: A single dose of 177Lu-J591 was well tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose response. Imaging biomarkers seem promising. Clin Cancer Res; 19(18); 5182–91. ©2013 AACR.
Intranuclear inclusions in a fragile X mosaic male
Authors: Dalyir I Pretto, Michael R Hunsaker, Christopher L Cunningham, Claudia M Greco, Randi J Hagerman, Stephen C Noctor, Deborah A Hall, Paul J Hagerman, Flora Tassone
Journal: Translational Neurodegeneration (2013)

Lack of the fragile X mental retardation protein leads to Fragile X syndrome (FXS) while increased levels of FMR1 mRNA, as those observed in premutation carriers can lead to Fragile X- associated tremor ataxia syndrome (FXTAS). Until recently, FXTAS had been observed only in carriers of an FMR1 premutation (55-200 CGG repeats); however the disorder has now been described in individuals carriers of an intermediate allele (45-54 CGG repeats) as well as in a subject with a full mutation with mosaicism.Here, we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles. Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype. We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis. In addition, a dramatic 90% depletion of both FMR1 mRNA and FMRP levels was observed in the blood, as normally observed in FXS cases, and an even greater depletion in the brain. A clinical report of this patient, at age 71, described neurodegenerative signs of parkinsonism that were likely, in retrospect, part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions, the hallmark pathology of FXTAS.The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles. In addition, based on symptoms and pathological and molecular evidence, this report suggests the need to redefine the diagnostic criteria of FXTAS.
Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial
Authors: Nina Wressnigg, Eva-Maria Pöllabauer, Gerald Aichinger, Daniel Portsmouth, Alexandra Löw-Baselli, Sandor Fritsch, Ian Livey, Brian A Crowe, Michael Schwendinger, Peter Brühl, Andreas Pilz, Thomas Dvorak, Julia Singer, Clair Firth, Benjamin Luft, Bernhard Schmitt, Markus Zeitlinger, Markus Müller, Herwig Kollaritsch, Maria Paulke-Korinek, Meral Esen, Peter G Kremsner, Hartmut J Ehrlich, P Noel Barrett
Journal: The Lancet Infectious Diseases (2013)
Prostate Cancer Risk Groups and Comparisons: Fruitless or Fruitful?
Authors: James R. Gray, Chaundre Cross, Anthony D’Amico
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.99.140 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12351616 Prostate Cancer Risk Groups and Comparisons: Fruitless or Fruitful? James R. GrayxJames R. GraySearch for articles by this author Chaundre CrossxChaundre CrossSearch for articles by this author , Anthony D’AmicoxAnthony D’AmicoSearch for articles by this author Show More Sarah Cannon Cancer Center, Nashville, TNBrigham and Women’s Hospital, Boston, MA https://doi.org/10.1200/JCO.2002.99.140 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01102002In Reply:We are thankful for the interest and comments on our study of race and prostate-specific antigen (PSA) outcome after radical prostatectomy for patients with clinically localized prostate cancer.1 We agree that beyond low risk, all risk categorizations may contain a heterogeneous patient population with regard to extent and biologic aggressiveness of the disease. However, we did apply a χ2 metric to test for differences in the proportion of African-American versus white men having a specific pretreatment PSA level, biopsy Gleason score, or clinical T category at diagnosis and did not find any statistically significant differences in the high- or low-risk groups, as shown in Table 2. With that said, there was a numerical but nonstatistically significant difference in PSA outcome among the two races in the high-risk group. This raises the question of whether a true difference in biology existed among the races or whether an imbalance in yet-to-be-defined predictive factors was present. Given the recent reports by Bianco et al2 and D’Amico et al3 in 2002 regarding stage migration due to the increased use of PSA-based screening, PSA outcome continues to improve across all races. Therefore, perhaps the numerical differences in PSA outcome across race as noted in the high-risk patients in this study will eventually disappear. Time will tell.1. Cross CK, Shultz D, Malkowicz SB, et al: Impact of race on prostate-specific antigen outcome after radical prostatectomy for clinically localized adenocarcinoma of the prostate. J Clin Oncol 20:: 2863,2002-2868, Link, Google Scholar2. Bianco FJ, Wood DP, Powell IJ, et al: Prostate cancer stage shift has eliminated the gap in disease-free survival in black and white American men after radical prostatectomy. J Urol 168:: 479,2002-482, Crossref, Medline, Google Scholar3. D’Amico AV, Chen M-H, Richie JP, et al: Changing natural history following surgery or radiation therapy for localized prostate cancer during the prostate-specific antigen era. Proc Am Soc Clin Oncol 21:: 176a,,2002 (abstr 702) Google Scholar
Effect of positive pressure breathing on lung lymph flow and water content in sheep.
Authors: W C Woolverton, K L Brigham, N C Staub
Journal: Circulation Research (1978)

We studied the effect of 10 cm H 2 O of continuous positive airway pressure breathing (CPAPB) on steady state lung fluid balance.In 9 of 20 chronically instrumented, unanesthetized sheep, we measured lung lymph flow, pulmonary vascular pressure, cardiac output, pleura!pressure, and lymph and plasma protein concentration during a 2-hour baseline period and 3-4 hours of CPAPB.In eight sheep, we measured the same variables after increasing average left atrial pressure by 18 cm H,O to cause mild interstitial edema.At the end of the final experiment, we anesthetized the sheep, removed the lungs, and measured their water content.During CPAPB, pleural and left atrial pressures increased by 5 cm H,O, whereas puhnonary artery pressure increased by 7-10 cm H 2 O. Lung lymph flow as well as lymph and plasma protein concentrations did not change significantly.In six sheep, postmortem lung water content was increased above that predicted but was within the predicted range for the group as a whole.We conclude that moderate CPAPB does not measurably affect the steady state lung fluid balance.More important, however, the rise in puhnonary vascular pressure must have been balanced by a rise in perimicrovascular interstitial fluid pressure since filtration did not change.It appears that the fraction of increased alveolar pressure transmitted to the microvessels was via the perimicrovascular fluid rather than through solid tissue contact.
Suicide Attempts in Patients With Bipolar I Disorder During Acute and Maintenance Phases of Intensive Treatment With Pharmacotherapy and Adjunctive Psychotherapy
Authors: Paola Rucci, Ellen Frank, Bryan Kostelnik, Andrea Fagiolini, Alan G. Mallinger, Holly A. Swartz, Michael E. Thase, Lori Siegel, Dorothy Wilson, David J. Kupfer
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Lifetime rates of suicide attempts among patients with bipolar I disorder were compared to rates during a 2-year period of intensive treatment with pharmacotherapy and with one of two adjunctive psychosocial interventions. METHOD: Subjects entered the study during an acute mood episode. Subjects were treated with primarily lithium pharmacotherapy and with either psychotherapy specific to bipolar disorder, which included help in regularizing daily routines, or nonspecific, intensive clinical management involving regular visits with empathic clinicians. Data on prior suicide attempts were obtained retrospectively from interviews with the NIMH-Life-Chart method. Data on suicide attempts during the clinical trial were collected systematically throughout the protocol. RESULTS: The rate of suicide attempts was 1.05 per 100 person-months before patients entered the trial. Patients experienced a threefold reduction in the rate of suicide attempts during the acute treatment phase (until the patient achieved stabilization, defined by completion of 4 weeks during which the patient had a mean score of ≤7 on the 17-item Hamilton Depression Rating Scale and ≤7 on the Bech-Rafaelsen Mania Scale) and a 17.5-fold reduction during maintenance treatment. Poisson loglinear regression analysis modeling the relationship between the observed rates and the three protocol stages (pretreatment, acute, and maintenance) showed that the reductions were significant in the acute and maintenance phases, compared with the pretreatment phase. No patient with one or more suicide attempts before entering the trial attempted suicide during the protocol. CONCLUSIONS: A treatment program in a maximally supportive clinical environment can significantly reduce suicidal behavior in high-risk patients with bipolar I disorder.
ECCRINE SWEATING IN PSORIASIS
Authors: OLIVE JOHNSON, SAM SHUSTER
Journal: British Journal of Dermatology (1969)

SUMMARY.— The lesions of psoriasis produce very much less sweat on pharmacological stimulation than clincally unaffected adjacent skin. The Na+ K+ concentrations of this sweat are very much decreased. The sweat rate increased after the lesions were stripped, sweat Na+ and K+ increased, but to a lesser extent. It is concluded that there are two abnormalities of sweat gland function in the plaques of psoriasis: (i) superficial obstruction of the ducts leading to hypohidrosis, (ii) an abnormality of absorption by the duct leading to inappropriately low sweat electrolyte concentration. The absence of miliaria despite duct blockage is discussed in relationship to the hypothesis that miliaria is due to an imbalance between the capacity of the coil to secrete and the ability of the duct to absorb.