tbuckley/cabot-search huggingface dataset:
Silencing of <i>DUOX</i> NADPH Oxidases by Promoter Hypermethylation in Lung Cancer
Authors: Sylvia Luxen, Steven A. Belinsky, Ulla G. Knaus
Journal: Cancer Research (2008)

Abstract The development of lung cancer is associated with aberrant promoter methylation and thus transcriptional silencing of many tumor suppressor genes or genes critical for cellular maintenance. Here we report that the NADPH oxidases DUOX1 and DUOX2, which are one of the main sources for reactive oxygen species production in the airway, are frequently silenced in human lung cancer. Screening of lung cancer cell lines revealed loss of DUOX1 and DUOX2 expression, which was restored after treatment with 5-aza 2′-deoxycytidine. Two genes, DUOXA1 and DUOXA2, which are transcriptionally and functionally linked to DUOX, also showed coordinated down-regulation in lung cancer cells and lung cancer specimen. Bisulfite sequencing and methylation-specific PCR revealed that CpG-rich promoter regions in both DUOX genes are hypermethylated. Epigenetic modification of at least one DUOX gene was detected in 50% of primary adenocarcinomas. Immunohistochemical analysis of airway sections derived from cancerous and matched healthy tissues confirmed down-regulation of Duox in the ciliated epithelial cells lining the respiratory tract. Reintroduction of functional Duox1 into lung cancer cell lines increased cell migration and wound repair without affecting cell growth. Our results suggest that an area on chromosome 15 that includes DUOX1, DUOX2, and their maturation factors is a frequent target for epigenetic silencing in lung cancer. [Cancer Res 2008;68(4):1037–45]
The role of glutaredoxin-1 in pulmonary inflammation induced by diesel exhaust particles
Authors: Sharen Provoost, Katrien De Grove, Ken Bracke, Guy Brusselle, Guy Joos, Tania Maes, Niki Reynaert
Journal: European Respiratory Journal (2013)

Rationale:  Inhalation of diesel exhaust particles (DEP) is associated with an oxidative and inflammatory response in the lung (Provoost et al., J Allergy Clin Immunol., 2012, 129: 483-491). Glutaredoxin-1 (GRX1) is a cytosolic enzyme that can regulate redox-dependent signalling cascades and pro-inflammatory transcription factors via modulation of protein glutathionylation. Here, we hypothesised that GRX1 regulates DEP-induced pulmonary inflammation.   Methods:  WT and GRX1 knockout (KO) mice were intratracheally instilled with saline or 100 µg DEP (SRM 2975) on day 1, 4 and 7. On day 9, inflammatory cell recruitment towards the bronchoalveolar lavage fluid (BALF) and lung tissue were examined by flow cytometry.   Results:  WT mice showed increased neutrophil recruitment towards BALF in response to DEP, which was augmented in GRX1 KO mice. The recruitment of monocytes and dendritic cells to BALF was comparable between DEP-exposed WT and GRX1 KO mice. In lung tissue, DEP-induced inflammation was not different between WT and GRX1 KO.   Conclusion:  GRX1 has a limited, but protective role in DEP-induced neutrophilic inflammation.   Funding:  Fund for Scientific Research Flanders - Belgium (FWO Vlaanderen; Research Project G.0329.11N), Interuniversity Attraction Poles (IUAP) - Belgian Science Policy P6/35 and P7/30 and Concerted Research Initiative of the Ghent University, Project No BOF/GOA 01G01009. Sharen Provoost is a post-doctoral researcher of the Fund for Scientific Research in Flanders (FWO Vlaanderen).
Human 1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by 1 1 integrin
Authors: A. Sudhakar
Journal: Journal of Clinical Investigation (2005)

Human noncollagenous domain 1 of the α1 chain of type IV collagen [α1(IV)NC1], or arresten, is derived from the carboxy terminal of type IV collagen. It was shown to inhibit angiogenesis and tumor growth in vivo; however, the mechanisms involved are not known. In the present study we demonstrate that human α1(IV)NC1 binds to α1β1 integrin, competes with type IV collagen binding to α1β1 integrin, and inhibits migration, proliferation, and tube formation by ECs. Also, α1(IV)NC1 pretreatment inhibited FAK/c-Raf/MEK/ERK1/2/p38 MAPK activation in ECs but had no effect on the PI3K/Akt pathway. In contrast, α1(IV)NC1 did not affect proliferation, migration, or the activation of FAK/c-Raf/MEK1/2/p38/ERK1 MAPK pathway in α1 integrin receptor knockout ECs. Consistent with this, α1(IV)NC1 elicited significant antiangiogenic effects and tumor growth inhibition in vivo but failed to do the same in α1 integrin receptor knockout mice. This suggests a highly specific, α1β1 integrin–dependent antiangiogenic activity of α1(IV)NC1. In addition, α1(IV)NC1 inhibited hypoxia-induced expression of hypoxia-inducible factor 1α and VEGF in ECs cultured on type IV collagen by inhibiting ERK1/2 and p38 activation. This unravels a hitherto unknown function of human α1(IV)NC1 and suggests a critical role for integrins in hypoxia and hypoxia-induced angiogenesis. Collectively, the above data indicate that α1(IV)NC1 is a potential therapeutic candidate for targeting tumor angiogenesis.
Sensitivity of Confluent and Cycling Embryonic Hamster Cells to Sulfur Mustard, 1,3-Bis(2-Chloroethyl)-1-Nitrosourea, and Actinomycin D&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Carolyn J. Thatcher, I. G. Walker
Journal: JNCI Journal of the National Cancer Institute (1969)

Transitions between the stationary, or confluent, state and the active, or cycling, state were examined for hamster embryo cells in vitro. Values of several cell parameters (fraction of cells synthesizing DNA, rate of DNA synthesis, amount of DNA per cell, growth rate) indicated that cells entered the stationary phase in G1 and then slowly doubled their DNA content without further division. The sensitivity to sulfur mustard or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) was not significantly different for active or confluent cells. Sensitivity to actinomycin D, however, was greater for confluent than for active cells. We conclude that the “stationary phase” of confluent hamster embryo cells does not correspond to the G0 of hematopoietic stem cells, and, furthermore, that a state of “no cell cycle” is not by itself sufficient to confer resistance to the drugs studied. The post-treatment ability to repair damage caused by sulfur mustard or BCNU was not enhanced by a state of “no cell cycle.”
Using Positron Emission Tomography Imaging for Maximum Benefit in Locally Advanced Cervical Cancer
Authors: Peter G. Rose
Journal: Journal of Clinical Oncology (2013)

Gouy et al 1 recently reported a prospective study in locally advanced cervical cancer in which patients with negative positron emission tomography-computed tomography (PET/CT) of the para-aortic (PA) area underwent laparoscopic PA staging.The authors found a 12% false negative rate of PET/CT in the PA region.Prognostic factors of PA nodal involvement included the presence of pelvic uptake on PET/CT.The authors found that the rate of pathologically positive PA nodes was 9% in those with negative pelvic lymph nodes and 24% in those with positive pelvic nodes by PET/CT.These rates are similar to those from other published reports. 2,3he implication for the radiation oncologist is multifold.In patients who are found to have positive pelvic nodes on PET/CT and do not undergo surgical PA staging, the risk of PA nodal involvement is sufficiently high to warrant extended field radiation therapy.In addition, there appears to be a subset of those with negative pelvic nodes by PET/CT who harbor PA nodal disease and may be receiving insufficient treatment.To clarify some of the practical ramifications, we have several questions for the authors.First, In the subset of patients with negative pelvic lymph nodes and positive PA nodes, what was ithe distribution of size of the nodal metastases?In the entire cohort, the authors found that those with PA nodal metastases Յ 5 mm had outcomes comparable to those without PA nodal disease.If the PA disease is primarily microscopic in the subset, perhaps it is reasonable to expect chemotherapy to sterilize this disease.Otherwise, perhaps treatment intensi-fication is required in a subset of those with radiographically nodenegative disease.Second, we are interested to learn whether the authors could identify any subset of patients with positive pelvic nodes in whom PA nodal irradiation may be excluded.We hypothesize that in patients with few involved pelvic lymph nodes or with lower location of pelvic nodal disease (as compared with common iliac nodal involvement), the risk of positive PA disease may be lower.Such data is important for optimal treatment decision making in these patients until the results of prospective randomized studies clarifying the role of PA nodal staging are available.
Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency
Authors: Bodo Grimbacher, Andreas Hutloff, Michael Schlesier, Erik Glocker, Klaus Warnatz, Ruth Dräger, Hermann Eibel, Beate Fischer, Alejandro A. Schäffer, Hans W. Mages, Richard A. Kroczek, Hans H. Peter
Journal: Nature Immunology (2003)
Phase III Randomized Intergroup Trial of Subtotal Lymphoid Irradiation Versus Doxorubicin, Vinblastine, and Subtotal Lymphoid Irradiation for Stage IA to IIA Hodgkin’s Disease
Authors: Oliver W. Press, Michael LeBlanc, Allen S. Lichter, Thomas M. Grogan, Joseph M. Unger, Todd H. Wasserman, Ellen R. Gaynor, Bruce A. Peterson, Thomas P. Miller, Richard I. Fisher
Journal: Journal of Clinical Oncology (2001)

PURPOSE: The management of early-stage Hodgkin’s disease in the United States is controversial. To evaluate whether staging laparotomy could be safely avoided in early-stage Hodgkin’s disease and whether chemotherapy should be a part of the treatment of nonlaparotomy staged patients, a phase III intergroup trial was performed. PATIENTS AND METHODS: Three hundred forty-eight patients with clinical stage IA to IIA supradiaphragmatic Hodgkin’s disease were randomized without staging laparotomy to treatment with either subtotal lymphoid irradiation (STLI) or combined-modality therapy (CMT) consisting of three cycles of doxorubicin and vinblastine followed by STLI. RESULTS: The study was closed at the second, planned, interim analysis because of a markedly superior failure-free survival (FFS) rate for patients on the CMT arm (94%) compared with the STLI arm (81%). With a median follow-up of 3.3 years, 10 patients have experienced relapse or died on the chemoradiotherapy arm, compared with 34 on the radiotherapy arm (P &lt; .001). Few deaths have occurred on either arm (three deaths on CMT and seven deaths on STLI). Treatment was well tolerated, with only one death on each arm attributed to treatment. CONCLUSION: These results demonstrate that it is possible to obtain a high FFS rate in a large group of stage IA to IIA patients without performing staging laparotomy and that three cycles of chemotherapy plus STLI provide a superior FFS compared with STLI alone. Extended follow-up is necessary to assess freedom from second relapse, overall survival, late toxicities, patterns of treatment failure, and quality of life.
The tumor dormant state. Comparison of L5178Y cells used to establish dormancy with those that emerge after its termination.
Authors: K J Weinhold, D A Miller, E F Wheelock
Journal: The Journal of Experimental Medicine (1979)

The tumor dormant state established in L5178Y immunized and challenged mice is characterized by a prolonged period of clinical normalcy followed by rapid tumor outgrowth. The tumor cells which emerged after termination of the tumor dormant state had abnormal marker chromosomes identical to those in the L5178Y cells used in the original challenge inoculum, indicating that the emergent tumor cells were progeny of the challenge inoculum. Original and emergent L5178Y cells had equivalent in vivo growth rates, when inoculated into normal DBA/2 mice. The emergent L5178Y cells were less susceptible than original cells to in vitro lysis by tumor dormant PC. Original and emergent L5178Y cells expressed common tumor-associated target antigens for cytolytic effector cells. Both modulation and masking of these target antigens were ruled out as mechanisms for decreased susceptibility to cell-mediated cytolysis. Immunofluorescence revealed heterogeneity in tumor-associated antigen expression within both original and emergent cell populations, with a decreased intensity of staining in the emergent population. Both populations were equally susceptible to lysis by alloimmune cells, alloantiserum, and anti-Thy 1.2 serum, but emergent cells were less susceptible to lysis by serum directed against L5178Y TAA. Quantitative absorption revealed that the emergent L5178Y cells expressed eightfold less serologically detectable TAA than the original cells. These findings indicate that the host immune response developing during establishment of the tumor dormant state selects a stable tumor cell subpopulation which expresses decreased amounts of surface tumor-associated target antigens.
Cryosurgery in old world cutaneous leishmaniasis
Authors: Y. Al-Gindan, R. Kubba, A.H.S. Omer, A.M. El-Hassan
Journal: British Journal of Dermatology (1988)

Journal Article Cryosurgery in old world cutaneous leishmaniasis Get access Y. Al‐Gindan, Y. Al‐Gindan College of Medicine King Faisal University P.O. Box 2 114, Dammam 31451 Saudi Arabia Search for other works by this author on: Oxford Academic Google Scholar R. Kubba, R. Kubba College of Medicine King Faisal University P.O. Box 2 114, Dammam 31451 Saudi Arabia Search for other works by this author on: Oxford Academic Google Scholar A.H.S. Omer, A.H.S. Omer College of Medicine King Faisal University P.O. Box 2 114, Dammam 31451 Saudi Arabia Search for other works by this author on: Oxford Academic Google Scholar A.M. El‐Hassan A.M. El‐Hassan College of Medicine King Faisal University P.O. Box 2 114, Dammam 31451 Saudi Arabia Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 118, Issue 6, 1 June 1988, Pages 851–854, https://doi.org/10.1111/j.1365-2133.1988.tb02605.x Published: 01 June 1988
I-E-linked control of spontaneous rheumatoid factor production in normal mice.
Authors: P Pereira, A Coutinho
Journal: The Journal of Experimental Medicine (1989)

The concentration of serum IgM molecules binding to IgG2a (rheumatoid factor [RF]) in solid phase assays is 10-100-fold higher in normal, unmanipulated C3H/HeJ (H-2k) than in C57BL/6 (H-2b) mice. Analysis of MHC-congenic mice with the prototype strains show that C3H SW (H-2b) are low, and B6.H-2k are high RF expressor strains, respectively. Furthermore, segregation of RF phenotypes in progenies from backcrosses to C3H/HeJ of (C3H/HeJ x C57BL/6)F1 hybrid mice shows MHC- and IgH-linked controls. RF phenotypes also segregate as if they are MHC linked in crosses between H-2-congenic strains (C3H/HeJ and C3H.SW). The study of intra-H-2 (k/b and k/s) recombinant mice suggested that RF phenotype control is linked to the I-E region. This was confirmed by the typing of C57BL/6 mice expressing a transgenic E alpha chain, and thus, I-E+, which, in contrast to nontransgenic littermates, are high expressors of RF.
Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non–Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy
Authors: Frances A. Shepherd, Janet Dancey, Rodryg Ramlau, Karin Mattson, Richard Gralla, Mark O’Rourke, Nathan Levitan, Laurent Gressot, Mark Vincent, Ronald Burkes, Susan Coughlin, Yong Kim, Jocelyne Berille
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non–small-cell lung cancer who had previously been treated with platinum-based chemotherapy. Secondary end points included assessment of response (docetaxel arm only), toxicity, and quality of life. PATIENTS AND METHODS: Patients with performance statuses of 0 to 2 and stage IIIB/IV non–small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters. They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel. Patients were stratified by performance status and best response to cisplatin chemotherapy and were then randomized to treatment with docetaxel 100 mg/m 2 (49 patients) or 75 mg/m 2 (55 patients) or best supportive care. Patients in both arms were assessed every 3 weeks. RESULTS: One hundred four patients (103 of whom were eligible for entry onto the study) were well balanced for prognostic factors. Of 84 patients with measurable lesions, six (7.1%) achieved partial responses (three patients at each dose level). Time to progression was longer for docetaxel patients than for best supportive care patients (10.6 v 6.7 weeks, respectively; P &lt; .001), as was median survival (7.0 v 4.6 months; log-rank test, P = .047). The difference was more significant for docetaxel 75 mg/m 2 patients, compared with corresponding best supportive care patients (7.5 v 4.6 months; log-rank test, P = .010; 1-year survival, 37% v 11%; χ 2 test, P = .003). Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m 2 , three of whom died, and in one patient treated with docetaxel 75 mg/m 2 . Grade 3 or 4 nonhematologic toxicity, with the exception of diarrhea, occurred at a similar rate in both the docetaxel and best supportive care groups. CONCLUSION: Treatment with docetaxel is associated with significant prolongation of survival, and at a dose of 75 mg/m 2 , the benefits of docetaxel therapy outweigh the risks.
PfSET10, a Plasmodium falciparum Methyltransferase, Maintains the Active var Gene in a Poised State during Parasite Division
Authors: Jennifer C. Volz, Richard Bártfai, Michaela Petter, Christine Langer, Gabrielle A. Josling, Takafumi Tsuboi, Frank Schwach, Jake Baum, Julian C. Rayner, Henk G. Stunnenberg, Michael F. Duffy, Alan F. Cowman
Journal: Cell Host & Microbe (2012)
Ca <sup>2+</sup> Sparks in Rabbit Ventricular Myocytes Evoked by Action Potentials
Authors: Masashi Inoue, John H.B. Bridge
Journal: Circulation Research (2003)

It is not clear how many L-type Ca2+ channels (LCCs) are required to ensure that a Ca2+ spark is triggered during a normal mammalian action potential (AP). We investigated this in rabbit ventricular myocytes by examining both the properties of sparks evoked by APs and the activity of LCCs. We measured Ca2+ sparks evoked by repeated APs with pipettes containing 2 mmol/L EGTA and single LCC activity in cell-attached patches depolarized to +50 mV using pipettes containing 110 mmol/L Ba2+. With 2 mmol/L Ca2+ in the external solution, we observed sparks at the beginning of every evoked AP at numerous locations. Each spark was observed repeatedly at a fixed location and began during a limited interval after the AP peak. These sparks occurred with a probability of approximately unity. However, the chance that an LCC does not open during the interval when a spark is triggered is quite high ( approximately 0.13). Therefore, because single channels open with a probability significantly lower than 1, more than one LCC must be available to ensure that sparks are triggered with a probability of approximately unity. We conclude that it is likely that a cluster of LCCs is involved in gating a cluster of ryanodine receptors at the beginning of an AP.
Association of Heart Rate Variability With Occupational and Environmental Exposure to Particulate Air Pollution
Authors: Shannon R. Magari, Russ Hauser, Joel Schwartz, Paige L. Williams, Thomas J. Smith, David C. Christiani
Journal: Circulation (2001)

Background Airborne particulate matter has been linked to excess morbidity and mortality. Recent attention has focused on the effects of particulate exposure on cardiac autonomic control. Inhaled particulates may affect the autonomic nervous system either directly, by eliciting a sympathetic stress response, or indirectly, through inflammatory cytokines produced in the lungs and released into the circulation. Methods and Results This longitudinal study examined the association of particulates ≤2.5 μm in diameter (PM 2.5 ) with heart rate variability (HRV) in an occupational cohort (N=40). Continuous monitoring of exposure and HR was performed during and away from work. PM 2.5 levels were higher than ambient levels typically reported in Boston, 0.167±3.205 mg/m 3 (geometric mean±geometric SD). We found a 2.66% decrease (95% CI, −3.75% to −1.58%) in the 5-minute SD of normal RR intervals (SDNN) for every 1 mg/m 3 increase in the 4-hour moving PM 2.5 average and a 1.02% increase (95% CI, 0.59% to 1.46%) in HR after adjusting for potential confounding factors. The decrease in SDNN became larger as the averaging interval increased. Conclusions Workers experienced altered cardiac autonomic control after exposure to occupational and environmental PM 2.5 . There appears to be either a long-acting (several hours) and a short-acting (several minutes) component to the mechanism of action that may be related to the production of cytokines and the sympathetic stress response, respectively, or a cumulative effect that begins shortly after exposure begins. The clinical significance of these effects in a healthy working population is unclear.
Garlic-Derived<i>S</i>-allylmercaptocysteine Is a Novel<i>In vivo</i>Antimetastatic Agent for Androgen-Independent Prostate Cancer
Authors: Edward W. Howard, Ming-Tat Ling, Chee Wai Chua, Hiu Wing Cheung, Xianghong Wang, Yong Chuan Wong
Journal: Clinical Cancer Research (2007)

Abstract Purpose: There is epidemiologic evidence that high garlic consumption decreases the incidence of prostate cancer, and compounds isolated from garlic have been shown to have cancer-preventive and tumor-suppressive effects. Recent in vitro studies in our laboratory have shown that garlic-derived organosulfur compound S-allylmercaptocysteine suppresses invasion and cell motility of androgen-independent prostate cancer cells via the up-regulation of cell-adhesion molecule E-cadherin. S-allylmercaptocysteine is therefore a potential antimetastatic drug with broad clinical applications that we tested in vivo for the first time in this study. Experimental Design: We used a newly established fluorescent orthotopic androgen-independent prostate cancer mouse model to assess the ability of S-allylmercaptocysteine to inhibit tumor growth and dissemination. Results: We showed that oral S-allylmercaptocysteine not only inhibited the growth of primary tumors by up to 71% (P &amp;lt; 0.001) but also reduced the number of lung and adrenal metastases by as much as 85.5% (P = 0.001) without causing notable toxicity. This metastatic suppression was accompanied by a 91% reduction of viable circulating tumor cells (P = 0.041), suggesting that S-allylmercaptocysteine prevents dissemination by decreasing tumor cell intravasation. Conclusions: Our results provide in vivo evidence supporting the potential use of S-allylmercaptocysteine as an E-cadherin up-regulating antimetastatic agent for the treatment of androgen-independent prostate cancer. This is the first report of the in vivo antimetastatic properties of garlic, which may also apply to other cancer types.