tbuckley/cabot-search huggingface dataset:
<scp>ADAM</scp>10 and Notch1 on murine dendritic cells control the development of type 2 immunity and IgE production
Authors: S. R. Damle, R. K. Martin, C. L. Cockburn, J. C. Lownik, J. A. Carlyon, A. D. Smith, D. H. Conrad
Journal: Allergy (2017)

Allergy and allergic asthma are significant health burdens in developed countries and are increasing in prevalence. Dendritic cells (DCs) initiate immune responses to common aeroallergens, and ADAM10 has been demonstrated to be important for the development of adaptive responses. This study's objective was to understand the role of ADAM10 on DCs in the development of allergic and anaphylactic responses.In this study, we used mouse models of allergic airway inflammation (house dust mice and Alternaria alternata) and OVA-induced models of active anaphylaxis to determine the DC-specific function of ADAM10 and Notch signaling. To examine TH 1 and TH 17 immunity infection with Anaplasma phagocytophilum and Citrobacter rodentium respectively, were used.Mice, which have ADAM10 deleted from DCs, have dramatic reductions in IgE production and do not develop significant TH 2 immune responses. Further, ADAM10DC-/- mice are resistant to IgE-mediated anaphylaxis. This response is selective for TH 2 immunity as TH 1 and TH 17 immunity is largely unaffected. Notch1, a known ADAM10 substrate, when knocked out of DCs (Notch1DC-/- ) demonstrated a similar reduction in anaphylaxis and IgE. Without ADAM10 and Notch1 signaling, DCs were unable to make cytokines that stimulate TH 2 cells and cytokines. Anaphylaxis and allergic lung inflammation were restored in ADAM10DC-/- with the overexpression of the Notch1-intracellular domain, confirming the role of Notch signaling.Targeting ADAM10 and Notch1 on DCs represent a novel strategy for modulating TH 2 immune responses and IgE production.
Abstract #18: Cellular responses to cancer chemopreventive agent D,L-sulforaphane in human prostate cancer cells are initiated by the mitochondria-derived reactive oxygen species
Authors: Eun-Ryeong Hahm, Dong Xiao, Jedrzej Antosiewicz, Anna Powolny, Ajay Bommareddy, Yan Zeng, Anna Herman-Antosiewicz, Shivendra Singh
Journal: Cancer Research (2009)

We have shown previously that D,L-sulforaphane (SFN), a synthetic cancer chemopreventive analogue of broccoli-derived isomer L-SFN, causes G2/M phase cell cycle arrest, apoptotic cell death, and autophagy in human prostate cancer cells. However, the mechanism by which SFN initiates these cellular responses remains elusive. We now demonstrate that cellular responses to SFN in LNCaP and PC-3 human prostate cancer cells are initiated by mitochondria-derived reactive oxygen species (ROS). Mitochondrial DNA deficient Rho-0 variants of LNCaP and PC-3 cells, generated by culture in the presence of sodium pyruvate, uridine, and ethidium bromide, were nearly completely resistant to SFN-mediated ROS generation, apoptosis, activation of caspase-3, collapse of mitochondrial membrane potential, and cytosolic release of cytochrome  c  compared with corresponding wild-type cells. The Rho-0 variant of PC-3 cell line also resisted SFN-mediated induction of Bax and down-modulation of Bcl-2 protein. Twenty-four hour exposure of wild-type cells to 20 µM SFN resulted in G2/M phase cell cycle arrest that was accompanied by accumulation of cyclin B1, hyperphosphorylation of cyclin-dependent kinase 1 (cdk1) and checkpoint kinase 2, and increased levels of Ser10 phosphorylated histone H3 (a marker of mitotic cells) and p21 (a cdk inhibitor). These effects were not observed in the Rho-0 variant of PC-3 cells. The SFN-induced autophagy, which serves to protect against apoptosis, was also partially but significantly suppressed in Rho-0 variants of LNCaP and PC-3 cells compared with respective wild-type cells as judged by cleavage of microtubule associated protein 1 light chain 3 (LC3) and formation of acidic vesicular organelles. Biochemical assays revealed statistically significant inhibition of complex I-linked NADH ubiquinone oxidoreductase and complex II-linked succinate-ubiquinone oxidoreductase activities in SFN-treated LNCaP and PC-3 cells. These results indicate that mitochondria-derived ROS serve to initiate cellular responses to SFN. Translational implication of these findings is that chemopreventive activity of SFN may be abrogated in the presence of antioxidants. This investigation was supported in part by the US PHS grants CA115498 and CA101753, awarded by the National Cancer Institute, USA (to S.V.S.) and grant 2718/P01/2007/32, awarded by the Polish Ministry of Science and Higher Education (to A.H.).   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 18.
Chemosensitivity and DNA repair in BRCA1 deficient murine mammary epithelial cells
Authors: Vandana B. Sharma, Anne-Renee Hartman, Magda K. Sgasias, Stephanie Turner, Kenneth H. Cowan, James M. Ford
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

4390 

Breast cancer is the second leading cause of cancer death among US women. Inherited mutations in the BRCA1 tumor suppressor gene result in a 50-85% lifetime risk for developing breast cancer and an increased risk for ovarian and prostate cancer. While these germline mutation carriers account for 5% of breast cancer cases, emerging evidence suggests that up to 30% of sporadic breast cancers exhibit epigenetic silencing of BRCA1 by promoter hypermethylation and other mechanisms. These BRCA1 associated tumors are frequently estrogen receptor (ER) negative and often carry mutations of the p53 tumor suppressor protein. The lack of ER renders BRCA1 deficient cancers ineffective targets of hormonal manipulations, therefore making chemotherapy the only treatment option available to patients with metastatic disease. The BRCA1 protein has been implicated in many cellular processes, yet its specific mechanism of tumor suppression remains unclear. BRCA1 plays a role in several DNA repair pathways including nucleotide excision repair (NER). We have demonstrated, by an MTT chemosensitivity assay, that Brca1 deficient murine mammary epithelial cells (MMECs) are 3-fold more sensitive to ultraviolet-C (UV-C) radiation, 10-fold more sensitive to cisplatin, and 25-fold more sensitive to gemcitabine chemotherapy than the isogenic, Brca1 positive parental cell line. In addition, Brca1 deficient cells demonstrate decreased repair of UV-C induced cyclobutane pyrimidine dimers in genomic DNA. Loss of Brca1 expression leads to blunted UV-C induced expression of the damaged-DNA binding proteins xeroderma pigmentosum complementation group C (XPC), but not DDB2, which is mutated in xeroderma pigmentosum complementation group E (XPE). These results confirm our earlier findings that Brca1 is involved in global genomic NER, and affects this process through regulation of DNA damage recognition protein gene expression. In addition, the altered chemosensitivity observed in BRCA1 deficient cells raises the possibility that individuals with BRCA1 deficient cancers may benefit from treatment with agents not traditionally used to treat breast cancer.
Proof-of concept phase I study of everolimus, letrozole and trastuzumab in hormone receptor-positive, HER2-positive/amplified or mutant metastatic breast cancer or other solid tumors: Evaluating synergy and overcoming resistance.
Authors: Shubham Pant, Jennifer J. Wheler, Siqing Fu, David S. Hong, Daniel D. Karp, Vivek Subbiah, Apostolia Maria Tsimberidou, Veronica R. Holley, Abenaa M. Brewster, Kimberly Higginbotham Koenig, Nuhad K. Ibrahim, Rashmi Krishna Murthy, Funda Meric-Bernstam, Filip Janku
Journal: Journal of Clinical Oncology (2017)

2583 Background: Preclinical models suggested synergistic antineoplastic activity of anti-estrogen therapy with HER2 and mTOR inhibitors. Methods: We designed a 3+3 dose escalation phase I study of the aromatase inhibitor letrozole 2.5mg PO daily, mTOR inhibitor everolimus 2.5-10mg PO daily and HER2 antibody trastuzumab 4-8mg loading dose followed by 2-4mg maintenance dose IV on day 1 of 21-day cycle in patients with hormone-receptor positive, HER2-positive/amplified or mutant advanced cancers (confirmed by immunohistochemistry and/or FISH and/or next-generation sequencing). The primary objectives were to determine maximum tolerated dose (MTD), dose limiting toxicities (DLT), overall safety and response. Results: A total of 18 patients (men, 1; women, 17; HER2 amplification, 14; HER2 mutation, 4; breast cancer, 15; ovarian cancer, 1; cervical cancer, 1; gastroesophageal junction cancer, 1), median age 56 years, median of 6 prior therapies (including letrozole [9] or other aromatase inhibitor [8]; everolimus [3]; trastuzumab [14] or other HER2 targeted therapy [1]) were enrolled in the planned 6 dose levels. The MTD has not been reached and grade 3 (G3) mucositis at the dose level 4 was the only DLT. Other G3 or G4 drug-related toxicities included G4 hyperglycemia in 1 patient, G3 hyperglycemia in 3 patients, G3 thrombocytopenia in 1 patient, G3 anemia in 1 patient and G3 headache in 1 patient. Of 18 patients, 3 (17%) had a partial response (all with heavily-pretreated breast cancer with HER2 amplification [2] or HER2 A775_G776insYVMA mutation [1]), 11 (61%) stable disease (SD) including 7 (39%) patients with SD &gt; 6 months (all with heavily-pretreated breast cancer), 3 (17%) progressed and 1 had pending evaluation. The median change in size of target lesions per RECIST 1.1. was -11% (-68% to +47%). Median progression-free survival was 9 months (95% CI 5.8-12.2). Conclusions: The combination of letrozole, everolimus and trastuzumab is well tolerated with encouraging activity in heavily-pretreated patients with HER2-amplified or mutant advanced breast cancer. Clinical trial information: NCT02152943.
Frequency and Prognostic Significance of the Presence of Additional Cytogenetic Abnormalitions (ACA) to the Philadelphia (Ph) Chromosome in Young Adults with ACUTE Lymphoblastic Leukemia (ALL) Treated with the ALL Ph08 Trial from the Pethema Group
Authors: Cristina Motlló, Josep-Maria Ribera, Mireia Morgades, Isabel Granada, Pau Montesinos, Santiago Mercadal, José González-Campos, Maria-José Moreno, Pere Barba, Marta Cervera, Manuel Barrios, Andrés Novo, Teresa Bernal, Jesus María Hernandez-Rivas, Eugenia Abella, Maria Luz Amigo, Mar Tormo, Rodrigo Martino, Esperanza Lavilla, Juan Bergua, Alfons Serrano, Daniel García-Belmonte, Ramon Guàrdia, Javier Grau, Evarist Feliu
Journal: Blood (2016)
Targeted Temperature Management After Cardiac Arrest
Authors: Clifton W. Callaway
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Effects of Inorganic Arsenic, Methylated Arsenicals, and Arsenobetaine on Atherosclerosis in the apoE−/− Mouse Model and the Role of As3mt-Mediated Methylation
Authors: Luis Fernando Negro Silva, Maryse Lemaire, Catherine A. Lemarié, Dany Plourde, Alicia M. Bolt, Christopher Chiavatti, D. Scott Bohle, Vesna Slavkovich, Joseph H. Graziano, Stéphanie Lehoux, Koren K. Mann
Journal: Environmental Health Perspectives (2017)

Arsenic is metabolized through a series of oxidative methylation reactions by arsenic (3) methyltransferase (As3MT) to yield methylated intermediates. Although arsenic exposure is known to increase the risk of atherosclerosis, the contribution of arsenic methylation and As3MT remains undefined.Our objective was to define whether methylated arsenic intermediates were proatherogenic and whether arsenic biotransformation by As3MT was required for arsenic-enhanced atherosclerosis.We utilized the apoE−/− mouse model to compare atherosclerotic plaque size and composition after inorganic arsenic, methylated arsenical, or arsenobetaine exposure in drinking water. We also generated apoE−/−/As3mt−/− double knockout mice to test whether As3MT-mediated biotransformation was required for the proatherogenic effects of inorganic arsenite. Furthermore, As3MT expression and function were assessed in in vitro cultures of plaque-resident cells. Finally, bone marrow transplantation studies were performed to define the contribution of As3MT-mediated methylation in different cell types to the development of atherosclerosis after inorganic arsenic exposure.We found that methylated arsenicals, but not arsenobetaine, are proatherogenic and that As3MT is required for arsenic to induce reactive oxygen species and promote atherosclerosis. Importantly, As3MT was expressed and functional in multiple plaque-resident cell types, and transplant studies indicated that As3MT is required in extrahepatic tissues to promote atherosclerosis.Taken together, our findings indicate that As3MT acts to promote cardiovascular toxicity of arsenic and suggest that human AS3MT SNPs that correlate with enzyme function could predict those most at risk to develop atherosclerosis among the millions that are exposed to arsenic. https://doi.org/10.1289/EHP806.
Oral Macrolides for the Dermatologic Manifestations of Blau Syndrome
Authors: Shalini Thareja, Kaitlyn Kollmann, Kaveh Ardalan, Marisa S. Klein-Gitelman, Amy S. Paller, Lisa M. Arkin
Journal: JAMA Dermatology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Plasma MHPG in depressive disorders and relationship to the dexamethasone suppression test
Authors: Roy A, Jimerson Dc, Pickar D
Journal: American Journal of Psychiatry (1986)

Plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in 51 depressed patients and 43 normal control subjects. There were significantly higher plasma MHPG levels in the combined patient group with current or past melancholia (N = 28) than in nonmelancholic (N = 12) or dysthymic (N = 11) patients, in unipolar melancholic (N = 16) versus bipolar melancholic (N = 4) patients, and in patients with a major depressive episode who failed to suppress cortisol after the dexamethasone suppression test (N = 24) versus patients with normal suppression (N = 16). Anxiety symptoms correlated significantly with plasma MHPG levels. These results substantiate previous evidence that dysregulation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system occur together in a subgroup of depressed patients.
Abstract 18957: Rationale, Design, and Analysis of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) - A Randomized, Placebo-Controlled Trial
Authors: Dick de Zeeuw, Bruce Neal, Vlado Perkovic, Kenneth W Mahaffey, Greg Fulcher, Mehul Desai, Jacqueline Yee, Wayne Shaw, Hsiaowei Deng, Elisa Fabbrini, Frank Vercruysse, Ngozi Erondu, David Matthews
Journal: Circulation (2016)

Introduction:  Inhibitors of sodium glucose co-transporter 2 (SGLT2) have been approved to treat patients with type 2 diabetes mellitus (T2DM), and the first large outcome trial to report on SGLT2 inhibitors demonstrated cardiovascular protection.   Hypothesis:  The CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) will test the effects of canagliflozin compared to placebo on the risk of kidney disease progression but will also provide substantial new insight into the effects of SGLT2 inhibition on vascular outcomes.   Methods:  CANVAS-R is a prospective, randomized, double-blind, placebo-controlled clinical trial that has randomized 5,812 patients with T2DM (HbA1c ≥7.0% and ≤10.5%) with a history or high risk of cardiovascular events (ClinicalTrials.gov, NCT01989754). Patients have been assigned (1:1) to once-daily placebo or canagliflozin 100 mg (with optional up-titration to 300 mg) for a planned average of 2.5 years follow-up. The primary outcome will be progression of albuminuria, for which the study has at least 90% power ( α  = 5%) to detect a 22% or greater reduction in risk. In conjunction with the CANVAS trial, there will be about 870 major adverse cardiovascular events accrued by trial completion, which will provide at least 80% power ( α  = 5%) to detect a risk reduction of 19% or greater.   Results:  Recruitment was completed in May 2015. Mean baseline age was 64 years, duration of diabetes was 14 years; HbA1c was 8.3%, and body mass index was 32 kg/m 2 . Participants are 37% female, and about 70% had a history of atherosclerotic cardiovascular disease. The trial is anticipated to complete follow-up in 2017 and report results shortly thereafter.   Conclusions:  CANVAS-R should clearly define the effect of canagliflozin on progression of albuminuria. In conjunction with the ongoing CANVAS trial, this study will also enable the post-marketing evaluation of the cardiovascular safety and efficacy of canagliflozin and add substantially to the evidence base describing the effects of SGLT2 inhibition on vascular outcomes.
Incidence, prevalence, mortality and causes of death in systemic sclerosis in Korea: a nationwide population‐based study
Authors: G.W. Kang, K.H. Jung, Y.S. Lee, H.J. Kim, D.Y. Yoon, S.H. Lee, H.J. Hann, K.H. Kim, S. Han, Y. Kim, D.S. Kim, H.S. Ahn
Journal: British Journal of Dermatology (2017)
Pesticide Exposure and Risk of Rheumatoid Arthritis among Licensed Male Pesticide Applicators in the Agricultural Health Study
Authors: Armando Meyer, Dale P. Sandler, Laura E. Beane Freeman, Jonathan N. Hofmann, Christine G. Parks
Journal: Environmental Health Perspectives (2017)

Background: The occupation of farming has been associated with rheumatoid arthritis (RA); pesticides may account for this association, but there are few studies. Objectives: We investigated associations between RA and use of pesticides in the Agricultural Health Study. Methods: The study sample was drawn from male pesticide applicators enrolled in 1993–1997 who provided questionnaire data at baseline and at least once during follow-up (over a median 18 y; interquartile range 16–19). Incident RA cases (n=220), confirmed by physicians or by self-reported use of disease-modifying antirheumatic drugs, were compared with noncases (n=26,134) who did not report RA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusting for enrollment age, state, smoking pack-years, and education. We evaluated the association of RA with the use of 46 pesticides and across 4 levels (never use and tertiles) of lifetime days of use for 16 pesticides with OR≥1.2 for ever use. Results: Incident RA was associated with ever use of fonofos (OR = 1.70; 95% CI: 1.22, 2.37), carbaryl (OR = 1.51; 95% CI: 1.03, 2.23), and chlorimuron ethyl (OR = 1.45; 95% CI: 1.01, 2.07) compared with never use. Statistically significant exposure–response trends in association with RA were observed for lifetime days of use of atrazine [ORtertile3= 1.62 (95% CI: 1.09, 2.40); ptrend=0.01] and toxaphene [ORtertile3= 2.42 (95% CI: 1.03, 5.68); ptrend=0.02]. Exposure–response was nonlinear for fonofos [ORtertile1= 2.27 (95% CI: 1.44, 3.57); ORtertile2= 0.98 (95% CI: 0.54, 1.80); ORtertile3= 2.10 (95% CI: 1.32, 3.36); ptrend=0.005] and suggestive for carbaryl (ptrend=0.053). Conclusions: Our results provide novel evidence of associations between exposure to some pesticides and RA in male farmers. https://doi.org/10.1289/EHP1013
Transcriptome Analysis Identified Significant Differences in Gene Expression Variability Between WM and IgM-MGUS BM B Cell Clones
Authors: Alessandra Trojani, Milena Lodola, Alessandra Tedeschi, Antonino Greco, Barbara Di Camillo, Tiziana Sanavia, Anna Maria Frustaci, Maddalena Mazzucchelli, Chiara Villa, Daniela Boselli, Enrica Morra, Roberto Cairoli
Journal: Blood (2016)
<i>MAPK</i> Pathway and <i>TERT</i> Promoter Gene Mutation Pattern and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 Cases
Authors: Xue Bai, Yan Kong, Zhihong Chi, Xinan Sheng, Chuanliang Cui, Xuan Wang, Lili Mao, Bixia Tang, Siming Li, Bin Lian, Xieqiao Yan, Li Zhou, Jie Dai, Jun Guo, Lu Si
Journal: Clinical Cancer Research (2017)

Purpose: Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathologic characteristics and disease prognosis in the Asian population.Experimental Design: A total of 2,793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and telomerase reverse transcriptase (TERT) promoter region by Sanger sequencing. Mutations were correlated to clinicopathologic features and overall survival.Results: The incidences of somatic mutations within the BRAF, NRAS, C-KIT, TERT-228, TERT-250, and PDGFRA genes were 23.7%, 10.4%, 8.0%, 5.9%, 5.5%, and 1.4%, respectively. Hotspot mutations accounted for 95.8% and 87.2% of BRAF and NRAS mutations, respectively; meanwhile, C-KIT and PDGFRA mutations showed more heterogeneity. BRAF, C-KIT, and NRAS mutations were mutually exclusive. BRAF, C-KIT, NRAS, and numbers of gene mutations of the MAPK pathway were all independent negative prognostic factors (P = 0.007, other P < 0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse overall survival (all P < 0.001), whereas in mucosal melanoma, only C-KIT was (P = 0.006). Although correlated with BRAF mutations (P = 0.001 and P < 0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with overall survival (P = 0.406 and 0.256, respectively).Conclusions: The MAPK pathway and TERT promoter gene mutations are differentially represented in the Asian population. Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be aimed directly at these poor-prognosis subpopulations for maximum potential impact. Clin Cancer Res; 23(20); 6120-7. ©2017 AACR.