tbuckley/cabot-search huggingface dataset:
Dual Role of the Antioxidant Enzyme Peroxiredoxin 6 in Skin Carcinogenesis
Authors: Frank Rolfs, Marcel Huber, Florian Gruber, Friederike Böhm, Herbert J. Pfister, Valery N. Bochkov, Erwin Tschachler, Reinhard Dummer, Daniel Hohl, Matthias Schäfer, Sabine Werner
Journal: Cancer Research (2013)

Abstract The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, particularly under stress conditions. We identified Prdx6 as an important player in different phases of skin carcinogenesis. Loss of Prdx6 in mice enhanced the susceptibility to skin tumorigenesis, whereas overexpression of Prdx6 in keratinocytes of transgenic mice had the opposite effect. The tumor-preventive effect of Prdx6, which was observed in a human papilloma virus 8–induced and a chemically induced tumor model, was not due to alterations in keratinocyte proliferation, apoptosis, or in the inflammatory response. Rather, endogenous and overexpressed Prdx6 reduced oxidative stress as reflected by the lower levels of oxidized phospholipids in the protumorigenic skin of Prdx6 transgenic mice and the higher levels in Prdx6-knockout mice than in control animals. In contrast to its beneficial effect in tumor prevention, overexpression of Prdx6 led to an acceleration of malignant progression of existing tumors, revealing a dual function of this enzyme in the pathogenesis of skin cancer. Finally, we found strong expression of PRDX6 in keratinocytes of normal human skin and in the tumor cells of squamous cell carcinomas, indicating a role of Prdx6 in human skin carcinogenesis. Taken together, our data point to the potential usefulness of Prdx6 activators or inhibitors for controlling different stages of skin carcinogenesis. Cancer Res; 73(11); 3460–9. ©2013 AACR.
High Graft CD8 Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning
Authors: Ran Reshef, Austin P. Huffman, Amy Gao, Marlise R. Luskin, Noelle V. Frey, Saar I. Gill, Elizabeth O. Hexner, Taku Kambayashi, Alison W. Loren, Selina M. Luger, James K. Mangan, Sunita D. Nasta, Lee P. Richman, Mary Sell, Edward A. Stadtmauer, Robert H. Vonderheide, Rosemarie Mick, David L. Porter
Journal: Journal of Clinical Oncology (2015)

To characterize the impact of graft T-cell composition on outcomes of reduced-intensity conditioned (RIC) allogeneic hematopoietic stem-cell transplantation (alloHSCT) in adults with hematologic malignancies.We evaluated associations between graft T-cell doses and outcomes in 200 patients who underwent RIC alloHSCT with a peripheral blood stem-cell graft. We then studied 21 alloHSCT donors to identify predictors of optimal graft T-cell content.Higher CD8 cell doses were associated with a lower risk for relapse (adjusted hazard ratio [aHR], 0.43; P = .009) and improved relapse-free survival (aHR, 0.50; P = .006) and overall survival (aHR, 0.57; P = .04) without a significant increase in graft-versus-host disease or nonrelapse mortality. A cutoff level of 0.72 × 10(8) CD8 cells per kilogram optimally segregated patients receiving CD8(hi) and CD8(lo) grafts with differing overall survival (P = .007). Donor age inversely correlated with graft CD8 dose. Consequently, older donors were unlikely to provide a CD8(hi) graft, whereas approximately half of younger donors provided CD8(hi) grafts. Compared with recipients of older sibling donor grafts (consistently containing CD8(lo) doses), survival was significantly better for recipients of younger unrelated donor grafts with CD8(hi) doses (P = .03), but not for recipients of younger unrelated donor CD8(lo) grafts (P = .28). In addition, graft CD8 content could be predicted by measuring the proportion of CD8 cells in a screening blood sample from stem-cell donors.Higher graft CD8 dose, which was restricted to young donors, predicted better survival in patients undergoing RIC alloHSCT.
The<i>Yersinia</i>outer protein M inhibits osteoclastogenesis<i>in vitro</i>and reduces bone destruction in hTNFtg mice<i>in vivo</i>
Authors: C Cromme, C Rüter, J Scharnert, G Kollias, M A Schmidt, T Pap, J Bertrand
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> One main phenomenon in rheumatoid arthritis (RA) is severe bone destruction, mainly mediated by osteoclasts in the arthritic joints. YopM is the outer protein M of <i>Yersinia</i> species. It has cell penetrating properties and can translocate into the cell by its two N-terminal α-helices. Interestingly, YopM is capable of downregulating inflammatory response in host tissues infected with <i>Yersinia</i>. Based on this dual function – the self-delivering ability and the anti-inflammatory properties – The authors investigated the effect of recombinant YopM on invitro osteoclast differentiation and bone destruction in the human tumour necrosis factor transgenic (hTNFtg) mouse model of RA. <h3>Methods</h3> Recombinant YopM was cloned into pET-24 b (+) expression vector, expressed in Bl21 cells and purified. The uptake of YopM into bone marrow macrophages (BMMs) and osteoclasts was analysed using Cy3-coupled YopM and laser scanning microscopy. The authors then studied the effect of YopM on osteoclastogenesis in an invitro osteoclast formation assay. To unravel the signalling pathways involved in the effects of YopM, the authors investigated the activation of extracellular-signal-regulated kinase, p-38, AKT and nuclear factor-κB (NF-κB) signalling by Western Blot analysis. With respect to a potential invivo application of YopM, the authors injected YopM-Cy5 in the hindpaws of hTNFtg mice and monitored its distribution by fluorescence reflection imaging (FRI). Finally, the authors treated hTNFtg mice with YopM and an inactive deletion mutant of YopM and recorded clinical parameters. In addition, histomorphometric analyses of joint destruction were performed in hindpaw sections. <h3>Results</h3> YopM penetrated the cell membrane of BMMs, but not osteoclasts invitro and accumulated in the cells. Most interestingly, incubation of BMMs with YopM resulted in a strong reduction of both, osteoclast precursors and mature osteoclasts. Studying the signaling pathways affected by YopM, the authors found that YopM reduced the TNF α induced activation of NF-κB by reducing the phosphorylation of IκB α. TNF α mediated phosphorylation of mitogen activated protein kinases and AKT, however, was not altered by YopM. As shown in FRI, YopM-Cy5 injected into the hindpaws was detectable during the monitored time of 48 h. YopM treated hTNFtg mice showed a delayed onset of paw swelling and histomorphometric analyses of the hindpaw sections revealed reduced bone destruction and inflammation in YopM treated hTNFtg mice in comparison to untreated hTNFtg mice. <h3>Conclusion</h3> These results suggest that YopM has the potential to reduce inflammation and bone destruction invivo. Therefore, the underlying mechanisms and functional properties of YopM may serve as basis for the development of novel strategies for the treatment of RA.
High-grade MRI bone oedema is common within the surgical field in rheumatoid arthritis patients undergoing joint replacement and is associated with osteitis in subchondral bone
Authors: F M McQueen, A Gao, M Ostergaard, A King, G Shalley, E Robinson, A Doyle, B Clark, N Dalbeth
Journal: Annals of the Rheumatic Diseases (2007)

MRI bone oedema has been observed in early and advanced RA and may represent a cellular infiltrate (osteitis) in subchondral bone. We studied MRI scans from RA patients undergoing surgery, seeking to identify regions of bone oedema and examine its histopathological equivalent in resected bone.Preoperative contrast-enhanced MRI scans were obtained in 11 RA patients scheduled for orthopaedic surgery to the hands/wrists or feet. In 9, MRI scans were scored by 2 readers for bone oedema (RAMRIS system). Its distribution with respect to surgical site was investigated. In 4 patients, 7 bone samples were examined for a cellular infiltrate, and this was compared with MRI bone oedema, scored for spatial extent and intensity.Inter-reader intraclass correlation coefficients for bone oedema were 0.51 (all sites) and 0.98 (bone samples for histology). Bone oedema was observed at 60% of surgical sites vs 38% of non-surgical sites. High-grade bone oedema (score >/=50% maximum) was strongly associated with the surgical field (OR 9.3 (3.5 to 24.2), p<0.0001). Bone oedema scores correlated with pain (r = 0.67, p = 0.048) and CRP (r = 0.86, p = 0.01). In 4 of the 7 bone samples, there was concordance between bone oedema and subchondral osteitis. In 3, there was no MRI bone oedema, and osteitis was "slight".High-grade MRI bone oedema was common within the field of intended surgery and associated with pain. There was concordance between the presence and severity of MRI bone oedema and osteitis on histology, with an MRI threshold effect due to differences in image resolution.
GPR56 Inhibits Melanoma Growth by Internalizing and Degrading Its Ligand TG2
Authors: Liquan Yang, Scott Friedland, Nancy Corson, Lei Xu
Journal: Cancer Research (2013)

Abstract Excessive accumulation of extracellular matrix (ECM) is a hallmark of tumor microenvironment and plays active roles during tumor progression. How this process is regulated and whether it is reversible for cancer treatment are outstanding questions. The adhesion G protein–coupled receptor GPR56 inhibits melanoma growth and binds to tissue transglutaminase (TG2), a major crosslinking enzyme in ECM. To understand the function of TG2 in GPR56-mediated melanoma inhibition, we performed xenograft studies in immunodeficient Tg2−/− mice. Our results revealed an antagonistic relationship between GPR56 and TG2 in melanoma, although TG2 and its crosslinking activity promote melanoma growth, GPR56 antagonizes this effect by internalizing and degrading it. The negative regulation of TG2 by GPR56 associates with the decreased deposition of a major ECM protein, fibronectin, and impaired accumulation of focal adhesion kinase, indicating that the GPR56–TG2 interaction regulates ECM deposition and cell–ECM adhesion. Taken together, our findings establish the roles of TG2 in GPR56-mediated melanoma inhibition. The uncovered antagonistic relationship between GPR56 and TG2 proposes a mechanism by which ECM accumulation/crosslinking in tumors may be reversed, and thus could have therapeutic potential for cancer control and treatment. Cancer Res; 74(4); 1022–31. ©2013 AACR.
Bladder cancer, 1996
Authors: D. L. Lamm, F. M. Torti
Journal: CA A Cancer Journal for Clinicians (1996)

In superficial Ta or T1 tumors intravesical chemotherapy can eradicate existing carcinoma in one third to one half of patients and reduce tumor recurrence by 12 to 15 percent, on average. Superficial bladder cancer is remarkably sensitive to immunotherapy, particularly BCG. The use of BCG eradicates about two thirds of papillary carcinoma and nearly 90 percent of carcinoma in situ and reduces tumor recurrence by an average of 40 percent. Data now suggest that BCG immunotherapy reduces long-term tumor recurrence, disease progression, and mortality. The proclivity for tumor recurrence makes superficial bladder cancer an ideal malignancy for the evaluation of chemoprevention, and preliminary data suggest that high doses of vitamins may also reduce tumor recurrence. In locally advanced T2b to T4, N0 or N1, M0 bladder cancer, substantial clinical responses can be achieved if chemotherapy is used prior to surgical resection of muscle-invasive tumor (neoadjuvant treatment). Controlled trials are necessary to ascertain whether neoadjuvant chemotherapy improves survival. The use of CMV prior to and concomitant with bladder irradiation is also encouraging, but will require randomized trials to clarify its role in the treatment of invasive, nonmetastatic cancer. Finally, trials suggest benefit for chemotherapy used adjuvantly (after cystectomy) for muscle-invasive bladder cancer. However, further investigation is necessary to clarify and confirm the role of chemotherapy in this setting before it can be recommended routinely for patients. In metastatic disease, chemotherapy with CMV or M-VAC with surgical resection of residual masses can produce a cohort of long-term survivors with advanced bladder cancer. How to increase this small but important population of patients is a question for further research.
Intragastric nitric oxide production in humans: measurements in expelled air.
Authors: J O Lundberg, E Weitzberg, J M Lundberg, K Alving
Journal: Gut (1994)

High values (800-6000 parts per billion) of nitric oxide (NO) in expelled air from the stomach were shown in humans by chemiluminescence technique. These NO values were more than 100 times higher than those found in orally exhaled air. Intragastric NO production is probably non-enzymatic, requiring an acidic environment, as NO in expelled air was reduced by 95% after pretreatment with the proton pump inhibitor omeprazole. Furthermore, large amounts of NO were formed in vitro from lettuce and saliva when placed in hydrogen chloride (pH &lt; 2). In conclusion, large amounts of NO are formed intragastrically in humans and this source of NO may be of importance for the integrity of the gastric mucosa in health and disease. Measurements of NO in expelled air might be of value as a non-invasive method for estimation of gastric acidity.
Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF 
Authors: C Eriksson
Journal: Annals of the Rheumatic Diseases (2004)

Research on autoantibody formation in patients treated with TNF alpha inhibitors has produced contradictory results.To study the prevalence of autoantibodies in patients with rheumatoid arthritis treated with the TNF alpha inhibitor infliximab.53 patients (48 female, 11 male) treated with infliximab for rheumatoid arthritis were followed for autoantibody production before treatment and after 14, 30, and 54 weeks. Six patients treated with etanercept were studied for comparison. The analyses included antibodies against nuclear antigens (ANA), extractable nuclear antigens, double stranded (ds)DNA (by ELISA, IIF on Crithidia luciliae for IgM and IgG, and Farr assay), nucleosomes, cardiolipin, smooth muscle, mitochondria, proteinase 3, and myeloperoxidase antigens.The number of patients treated with infliximab who developed antibodies against dsDNA of both IgG and IgM class (tested by IIF) increased significantly. The prevalence of patients positive for IgG class increased to 66% at 30 weeks and 45% at 54 weeks, and of IgM class to 85% and 70%, respectively. The titre and number of patients expressing antibodies against nucleosomes and ANA also increased significantly. The number of rheumatoid factor or anticardiolipin positive patients was stable and there was no increase in antibodies against the other antigens. A lupus-like syndrome was seen in one patient. No patient treated with etanercept developed any of these autoantibodies.Patients treated with infliximab may develop anti-dsDNA antibodies of both IgM and IgG class, anti-nucleosome antibodies, and ANA, with a gradual increase until 30 weeks.
Computer Simulation of the Propagation Process in Excitation of the Ventricles
Authors: MITSUHARU OKAJIMA, TETSURO FUJINO, TOSHIJI KOBAYASHI, KAZUO YAMADA
Journal: Circulation Research (1968)

Simulation by a digital computer of propagated excitation in the ventricular myocardium has been accomplished. Experience with the program in normal conduction and in one example of abnormal conduction, an extrasystole, is presented. Results of the simulation process were in harmony with observations in animal experiments. This justifies attempts to apply this scheme to the analysis of abnormal ventricular excitation caused by other disturbances. A crucial role of the Purkinje network in determining the course of excitation spread was recognized in the simulated process of both normal beats and extrasystoles. New knowledge is expected from this scheme when applied to other types of abnormal excitation. The possibility of combining the scheme with a method of reconstruction of QRS complexes by means of "transfer impedance" values was pointed out.
Adenylyl cyclase, G proteins, and synaptic plasticity
Authors: Mark M. Rasenick
Journal: Behavioral and Brain Sciences (1995)

Abstract It has been suggested that type I adenylyl cyclase may play a unique role in long-term potentiation, due to both unique regulatory properties as well as a specialized distribution within the mammalian brain. This would allow an integration of the signals wrought by increased intracellular calcium with those conveyed into the cellular milieu via increased cAMP. These results are discussed in the context of changes in cellular structure, because of changing interactions between G proteins and cytoskeletal components, which might be expected to accompany chronic synaptic activation.
A Phase I Safety and Pharmacologic Study of a Twice Weekly Dosing Regimen of the Oral Taxane BMS-275183
Authors: Linda E. Bröker, Stephan A. Veltkamp, Elisabeth I. Heath, Bart C. Kuenen, Helen Gall, Ludovic Astier, Susan Parker, Louis Kayitalire, Patricia M. Lorusso, Jan H.M. Schellens, Giuseppe Giaccone
Journal: Clinical Cancer Research (2007)

Abstract Purpose: BMS-275183, an orally administered C-4 methyl carbonate paclitaxel analogue, showed promising activity in a phase I trial investigating a weekly treatment regimen, but was associated with a relatively high incidence of neuropathic side effects. The current dose escalation phase I trial was initiated to investigate whether twice weekly administration of BMS-275183 would improve its safety and tolerability. Additionally, the pharmacokinetics and possible antitumor activity were studied. Experimental Design: A cycle consisted of 4 weeks (i.e., eight twice weekly oral doses). The starting dose was 60 mg/m2 and the dose was increased by 20 mg/m2 increments. Cohorts consisted of three patients and were expanded to at least six patients when toxicity was encountered. Plasma pharmacokinetics were done on days 1 and 15. Results: A total of 38 patients were enrolled. The maximum tolerated dose was 100 mg/m2 twice weekly. Seventeen patients were treated at the maximum tolerated dose; 3 of 17 patients experienced a dose-limiting toxicity, consisting of a combination of neutropenia, neuropathy, and diarrhea. BMS-275183 seemed to have a considerably lower incidence of neuropathic side effects compared with the weekly treatment regimen. Confirmed partial responses were observed in two patients with non–small cell lung cancer, one patient with prostate cancer, and one patient with melanoma. In addition, a long-lasting prostate-specific antigen response was observed in a patient with prostate carcinoma with nonmeasurable disease. Conclusions: BMS-275183 is preferably given in a twice weekly regimen and has considerable antitumor activity. A phase II trial in non–small cell lung cancer using the twice weekly schedule has been initiated.
Nutritional status in patients with rheumatoid arthritis.
Authors: R Burnham, A S Russell
Journal: Annals of the Rheumatic Diseases (1986)

Intra-articular injection ofNutritional status in patients with phenylbutazone in gonarthrosis rheumatoid arthritis SIR, Between 1970 and 1986 we treated 15 patients suffering from severe chronic osteoarthritis of the knee with intra-articular injections of phenylbutazone.All were seen in our outpatient clinic with severely painful knees with effusion.Blood tests, synovial fluid analysis, including polarised light microscopic examination for crystals, and x rays confirmed the clinical diagnosis of osteoarthritis.They were treated successively with aspirin nonsteroidal anti-inflammatory drugs, physiotherapy, and intra-articular injections of steroids, all without success.Intra-articular injections at first were given monthly, injecting 5 mg dexamethasone or 20 mg triamcinalone after draining the joint.As there was no improvement after three injections we gave three more injections twice monthly, again without success.The treatment was therefore continued with weekly injections during the three following months.Despite these 16 injections 15 patients still had a painful swollen knee.These patients were offered the choice of continuing with the steroid injections (though we were reluctant to do so because of the possible side effects) or having injections of an anti-inflammatory drug in the hope of 'drying up' the effusion.They all volunteered to try the latter procedure.Again the knee was aspirated, but care was taken to leave about 10 ml synovial fluid in the joint so that the injected drugs would be diluted.We injected 1 ml phenylbutazone (190 mg) mixed with 5 ml procaine 1%.Among the 15 patients, three experienced no pain at injection, but 12 declared the procedure moderately painful.Pain lasted for about one hour.The patients returned for a check after one week.All were improved but not cured.Four required one more injection and 11 patients two more injections.In all cases effusion and pain subsided.Follow up has lasted from a few months to 10 years with no reappearance of the symptoms.Unfortunately we did not obtain synovial biopsy specimens.In view of the good clinical results we believe that intra- articular injections of phenylbutazone in severe knee osteoarthritis with effusion is a helpful procedure.We were unable to find any previous report on this subject, but SArkozi and Bartosiewicz reported a case of chondrocalcinosis treated successfully with this procedure.
Nifedipine therapy for Prinzmetal's angina.
Authors: J E Muller, S J Gunther
Journal: Circulation (1978)

A case is described in which nifedipine, a new coronary vasodilator, was effective in relieving attacks of Prinzmetal's angina unresponsive to conventional therapy. The extreme frequency of the anginal attacks provided evidence that lower doses of nifedipine lost their effectiveness approximately 4 hours after administration. A month after initiation of nifedipine, nitrates were withdrawn since they had been ineffective in controlling the attacks. A myocardial infarction occurred immediately, presumably due to coronary spasm.
Influence of alterations in sinus rate on determination of drug-induced changes in ventricular automaticity
Authors: R. D. WILKERSON, J. K. PRUETT
Journal: Cardiovascular Research (1978)

Journal Article Influence of alterations in sinus rate on determination of drug-induced changes in ventricular automaticity Get access R. DOUGLAS WILKERSON, R. DOUGLAS WILKERSON 1 From the Department of Pharmacology, University of South Alabama College of Medicine, and the Department of Pharmacology, Medical University of South Carolina, USA 1Address for reprints: Dr R. D. Wilkerson, Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, Alabama 36688, USA. Search for other works by this author on: Oxford Academic PubMed Google Scholar JACK K. PRUETT JACK K. PRUETT From the Department of Pharmacology, University of South Alabama College of Medicine, and the Department of Pharmacology, Medical University of South Carolina, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 12, Issue 1, January 1978, Pages 34–41, https://doi.org/10.1093/cvr/12.1.34 Published: 01 January 1978